Digital Therapy

Abstract

The subject matter disclosed herein relates to the field of digital therapies for increasing neural connectivity, improving immune function, and improving motor skills. The primary mode of providing digital therapies is the use of sensory means, including sensory inhibition, sensory substitution, sensory integration, or combinations thereof. Various digital interventions, methods and systems in digital therapies related thereto are disclosed herein. The present invention also provides combination therapies including digital interventions and non-digital interventions such as pharmaceutical agents.

Description

[Technical Field]

[0001] Related fields The subject matter disclosed herein relates to the field of digital therapies for increasing neural connectivity, improving immune function, and improving motor skills. The primary mode of providing digital therapies is the use of sensory means, including sensory inhibition, sensory substitution, sensory integration, or a combination thereof. Various digital interventions, methods and systems in digital therapies related thereto are disclosed herein. The present invention also provides combination therapies including digital interventions and non-digital interventions such as pharmaceutical agents. [Background technology]

[0002] In today's digital age, the role of digital therapies in supporting brain function is gaining recognition and importance. As smartphones, tablets, and computers become ubiquitous in our lives, digital therapies offer a convenient and accessible pathway to improving mental well-being. Scientific research shows that these digital interventions can have significant effects on brain function, ranging from reducing symptoms of anxiety and depression to enhancing cognitive abilities. As more people turn to digital platforms for mental health support, understanding the impact of digital therapies on brain function becomes increasingly important.

[0003] For the ease of demonstrating the usefulness of the present invention, this description focuses primarily on neurodegenerative diseases such as Alzheimer's disease ("AD"), which is the most common type of dementia. However, the primary approaches and tools for treating AD described herein can also be implemented in mild cognitive impairment (MCI), which is an early stage of memory loss or other cognitive impairment in individuals who retain the ability to independently perform most activities of daily living, as well as in other types of dementia and neurodegenerative disorders involving cognitive decline.

[0004] Remepy is a company that develops digital therapeutic platforms. Remepy's Digital Molecule® (DM) is based on cognitive and psychological digital interventions. DM induces physiological processes that balance the immune system and enhance brain neuroplasticity.

[0005] The objectives of this invention include the following: - To study medical conditions with unmet needs, - Identify psychological and cognitive interventions that have demonstrated desirable outcomes. -Verify the effects through MRI imaging and advanced blood sample analysis. - Digitizing intervention and treatment protocols into a platform and mobile app, such as the "Remepy" platform. - Designing coordinated treatment protocols and interventions, -Enhancing pharmaceuticals using software is To improve the efficacy of pharmaceuticals by activating brain mechanisms that modulate the immune system and increase synaptic connectivity and neural plasticity.

[0006] Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by cognitive decline, memory loss, and a decline in the ability to perform daily activities. AD is the most common form of dementia and affects millions of people worldwide. The defining features of AD are primarily the accumulation of abnormal protein deposits in the brain, including neurofibrillary tangles composed of beta-amyloid plaques and tau-amyloid fibrils. These features can be present up to 20 years before a patient shows changes in memory, thinking, or behavior. The exact pathogenesis of AD is still not fully understood, but at least some scientists now suggest that beta-amyloid protein, abnormal tau protein, or possibly both, play a significant role in the development of the disease.

[0007] Beta-amyloid plaques are thought to be a major contributing factor to disease development because they induce inflammation and oxidative stress, which can lead to damage and death of brain cells. Plaque accumulation may also induce the formation of neurofibrillary tangles and activate microglia cells.

[0008] Neurofibrillary tangles are formed by the accumulation of hyperphosphorylated tau protein in brain cells. Tau protein plays a crucial role in maintaining the structural integrity of neurons. The presence of tau protein in neurofibrillary tangles can lead to the loss of their normal function (leading to neuronal dysfunction and death) and may also trigger the activation of microglia.

[0009] Neuroinflammation plays a significant role in the pathogenesis of Alzheimer's disease (AD). Numerous studies have shown that microglia, a population of innate immune cells present in the central nervous system (CNS) and acting as the first line of defense against invading pathogens, drive persistent neuroinflammation and irreversible tissue damage in neurodegenerative disorders. Microglia are activated by the presence of amyloid plaques and neurofibrillary tangles. Microglial activation can contribute to disease progression by producing pro-inflammatory molecules and reactive oxygen species, which can lead to synaptic dysfunction, neuronal death, and inhibition of neurogenesis. In particular, in patients with Alzheimer's disease, reactive microglia have been shown to co-localize closely with amyloid plaques, suggesting an interaction between these two key pathological features. Microglial activation is suggested to act as a bridge to the pathological phosphorylation and aggregation of tau protein through a successive increase in amyloid plaques, microglial activation, and neurofibrillary tangles.

[0010] The brain changes described above in AD patients result in synaptic loss and neurodegeneration, which leads to a general and progressive loss of cognitive function. Initially, Alzheimer's disease typically destroys neurons and their connections in parts of the brain involved in memory, including the entorhinal cortex and hippocampus. Subsequently, it affects areas of the cerebral cortex responsible for language, reasoning, and social behavior. Overall, AD is characterized by impaired multisensory integration and intersensory connectivity, as well as memory loss and spatial perception, along with impaired connectivity and neuronal death between brain regions.

[0011] At the molecular level, AD manifests as widespread proteomic signs of synaptic gene downregulation across multiple brain regions and synaptic stress or breakdown in the cerebrospinal fluid (CSF) or blood.

[0012] According to the World Health Organization (WHO), dementia is the seventh leading cause of death globally, causing 1.6 million deaths in 2019 and costing a staggering $1.3 trillion worldwide. Even more alarming is the rapid increase in this figure, making dementia the fastest-growing cause of death globally. The annual cost per patient increases with the severity of the disease, meaning that the aging population reaching the later stages of dementia is placing an additional burden on the system. As a result, the global cost of dementia is projected to reach $2.8 trillion by 2030.

[0013] Currently, there are no treatments that can prevent or cure cognitive disorders. Treatment for Alzheimer's disease currently involves managing the patient's symptoms and well-being. While widely used treatments cannot prevent or slow disease progression, some drugs that target cognitive symptoms can alleviate or stabilize a patient's condition for a limited period. These include cholinesterase inhibitors such as donepezil or glutamate modulators like memantine (NMDA antagonists), all of which were first approved about 20 years ago. Since the approval of cholinesterase inhibitors, there have been numerous attempts to target disease progression with novel therapies. However, it is commonplace for large-scale phase 3 clinical trials to fail, often following mixed signals in phase 2.

[0014] In 2021, the U.S. Food and Drug Administration (FDA) approved aducanumab, an anti-amyloid antibody for early Alzheimer's disease, despite a lack of clear clinical evidence demonstrating the drug's cognitive benefit. A second anti-amyloid antibody, recanemab, was approved in 2023. However, the Centers for Medicare and Medicaid Services (CMS) recently announced that it would only compensate individuals enrolled in clinical trials and would limit compensation for future anti-amyloid antibodies based on the drugs' high risk-benefit profiles.

[0015] In July 2023, lecanemab became the first amyloid-beta-targeted antibody to be converted by the FDA from accelerated approval to standard approval for the treatment of Alzheimer's disease, following a determination that confirmatory trials validated clinical benefit. Lecanemab is approved for patients with mild cognitive impairment or mild cognitive impairment in Alzheimer's disease, the population for which the treatment was considered in clinical trials. The treatment is eligible for Medicare / Medicaid coverage under certain conditions.

[0016] Therefore, the present disclosure provides a method for increasing neuroplasticity in an individual, primarily through a digital platform. Data is provided throughout to demonstrate the effectiveness of the digital treatment plan of the present invention. As will become apparent, the benefits of digital therapeutic interventions extend beyond merely neurological and are also related to immune-related diseases and corresponding interventions. The present invention discloses aspects of personalization and combination with pharmacological treatment to improve patient outcomes. Summary of the Invention

[0017] In one embodiment, the present invention provides a method for increasing neural connectivity in an individual, the method comprising the individual performing at least one digital intervention of sensory suppression, sensory substitution, sensory integration, or a combination thereof.

[0018] In one embodiment, the at least one digital intervention is included within a digital therapeutic intervention plan. In one embodiment, the digital intervention includes at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof. In one embodiment, the at least one digital intervention is at least partially performed on a personal electronic device. In one embodiment, the method further comprises transferring data for the individual, where the data is selected from personal information, demographic information, medical information, biomarker information, pharmaceutical intake and dosing regimens, geographic information, environmental information, lifestyle information, health and well-being, biometric information, behavioral information, digital intervention-related data, goal setting, medical considerations, health and well-being, preferences, availability, time constraints, scheduling, personal strengths and weaknesses, cultural considerations, communication channel preferences, feedback from the individual, feedback from a healthcare provider, or a combination thereof.

[0019] In one embodiment, the method further includes analyzing data by machine learning, artificial intelligence (AI), statistical modeling, or a combination thereof, in order to adapt the digital therapeutic intervention plan. In one embodiment, the analysis determines the degree of improvement to be achieved by the individual implementing the digital therapeutic intervention plan. In one embodiment, the method further includes providing instructions to the individual before, during, and / or after any stage of the digital therapeutic intervention plan.

[0020] In one embodiment, at least one psychological intervention is selected from guided imaging, psychoeducation, psychotherapy, cognitive behavioral therapy, stress and anxiety management training, mindfulness-based interventions, body scanning training, sleep hygiene, fatigue training, Acceptance and Commitment Therapy (ACT), Dialectical Behavior Therapy (DBT), psychodynamic therapy, Solution-Focused Brief Therapy (SFBT), narrative therapy, pain therapy, addiction therapy, Gestalt therapy, behavioral activation therapy, telepsychiatry and teletherapy, or a combination thereof.

[0021] In one embodiment, at least one cognitive intervention is selected from maze navigation, spatial navigation, Magic 7 training, memory enhancement techniques, attention training, problem solving, sonification exercises, data visualization, geometric puzzles, shape and pattern matching, visual cognitive tasks, spatial reasoning games, face detection training, drawing games, concentration training, reading comprehension training, or any combination thereof.

[0022] In one embodiment, at least one physical intervention is selected from physiotherapy, voice therapy, speech therapy, swallowing therapy, breathing training, saliva and drooling therapy, chewing therapy, facial expression training, tremor management, mobility training, freeze and stiffness exercises, tapping training, limb agility exercises, volume-sustain-pitch training, training for gait freeze, motor function therapy, dance therapy, handwriting training, balance exercises, postural stability training, muscle training, stretching exercises, coordination training, metronome training, fine motor skills training, or a combination thereof.

[0023] In one embodiment, the maze is selected from a Hebb-Williams maze, a Morris water maze, a Burns maze, a radial arm maze, a T-maze, and an elevated plus maze. In one embodiment, sensory inhibition includes at least a partial reduction of at least one sensory modal input.

[0024] In one embodiment, at least one sensory modal input is selected from visual, auditory, and tactile. In one embodiment, sensory substitution includes at least partial substitution of at least one sensory modal input with at least one other sensory modal input.

[0025] In one embodiment, at least partial substitution of at least one sensory modality input by at least one other sensory modality input is From sight to hearing and / or touch, From hearing to sight and / or touch, The sense of touch is selected from sight and / or hearing.

[0026] In one embodiment, sensory integration includes at least a partial combination of at least two sensory modality group inputs. In one embodiment, the at least two sensory modality inputs are selected from visual, auditory, and tactile. In one embodiment, the digital intervention includes the individual interacting with a personal electronic device using any of the following means selected from touch gestures, motion gestures, voice commands, text input, camera and media interaction, sensor-based interaction, or a combination thereof. In one embodiment, touch gestures are selected from tapping, swiping, scrolling, pinching, dragging, double tapping, or a combination thereof. In one embodiment, motion gestures are selected from tilting, shaking, rotating, body movements, weaving, or a combination thereof.

[0027] In one embodiment, camera and / or media interaction may be selected from taking photographs, recording videos, uploading / downloading images, uploading / downloading audio, uploading / downloading videos, augmented reality, or a combination thereof. In one embodiment, sensor-based interaction may be performed by a global positioning system (GPS) system, an accelerometer, a gyroscope, a proximity sensor, or a combination thereof.

[0028] In one embodiment, at least one digital intervention is carried out in the form of an instructional video, an interactive video including input and feedback from an individual, a game, an instructional prompt, a question-and-answer survey with feedback, virtual reality, augmented reality, or a combination thereof.

[0029] In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, extends over a period ranging from 1 second to 60 minutes. In one embodiment, the digital therapeutic intervention plan is implemented over a period ranging from 1 day to 10 years. In one embodiment, the method further includes an adaptation plan during the course of the digital therapeutic intervention plan, and the method Receiving data and, Receiving updated data in accordance with at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, Analyzing data and updated data using machine learning, artificial intelligence (AI), or statistical modeling, This includes generating updated digital therapeutic intervention plans for individuals based on the analysis of updated data.

[0030] In one embodiment, the adaptation includes changes in any of the following, selected from: the type of intervention, the order of interventions, the frequency of interventions, the intensity of interventions, the length of interventions, the difficulty of interventions, the sensory modal inputs used, the level of interaction, or a combination thereof.

[0031] In one embodiment, the method further includes at least one additional device selected from a health monitoring system, medical device, haptic device, external speaker, headphones, virtual reality set, augmented reality glasses / device, biofeedback sensor, wearable activity tracker, smartphone, personal computing device, smart speaker, voice assistant, motion tracking sensor, virtual assistant system, internet hub, or a combination thereof, wherein the at least one additional device is configured to transfer data between a person, a personal electronic device, or a combination thereof.

[0032] In one embodiment, the health monitoring system is selected from wearable fitness trackers, remote patient monitoring (RPM) systems, telemedicine platforms, smart health devices, health and wellness apps, and hospital information systems (HIS).

[0033] In one embodiment, at least one additional device is configured to provide at least one of the following: real-time feedback to the individual based on collected data and interactions, measurement of health parameters, outputting signals to the individual, real-time customization of digital therapeutic intervention plans, monitoring the individual's engagement with and adherence to therapeutic protocols, remote monitoring, inter-device cloud synchronization and data sharing, or a combination thereof.

[0034] In one embodiment, a personal electronic device, at least one additional device, or a combination thereof, is configured to provide a sensory modal input for performing sensory inhibition, sensory substitution, sensory integration, or a combination thereof.

[0035] In one embodiment, the method is for treating, preventing, or alleviating symptoms in an individual suffering from a neurodegenerative disease.

[0036] In one embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, chronic traumatic encephalopathy (CTE), Lewy body dementia (LBD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), Huntington's disease, Creutzfeldt-Jakob disease, and Wilson's disease.

[0037] In one embodiment, the method is for treating, preventing, or alleviating symptoms in an individual suffering from a neurological disorder. In one embodiment, the method is for use in treating, preventing, or alleviating symptoms in an individual suffering from a neurological disorder.

[0038] In one embodiment, the neurological disorder is selected from mild cognitive impairment (MCI), sleep disorders, migraines and headache disorders, neuropathy, epilepsy, traumatic brain injury, spinal cord injury, and cerebrovascular disease.

[0039] In one embodiment, the method is for treating, preventing, or alleviating symptoms in an individual suffering from a psychological disorder. In one embodiment, the method is for use in treating, preventing, or alleviating symptoms in an individual suffering from a psychological disorder.

[0040] In one embodiment, the psychological disorder is selected from depression, anxiety, bipolar disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), attention-deficit / hyperactivity disorder (ADHD), eating disorders, substance use disorders, sleep disorders, autism spectrum disorder (ASD), personality disorders, schizophrenia, and dissociative disorders.

[0041] In one embodiment, the present invention provides a method for increasing neural connectivity in an individual, and this method is Individuals performing at least one digital intervention from sensory inhibition, sensory substitution, sensory integration, or a combination thereof, This includes administering at least one non-digital medical intervention before, during, or after at least one digital intervention, or a combination thereof.

[0042] In one embodiment, at least one digital intervention is included in the digital therapeutic intervention plan. In one embodiment, the digital intervention includes at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof. In one embodiment, at least one digital intervention is performed at least partially on a personal electronic device.

[0043] In one embodiment, the method further includes transferring data for an individual, wherein the data is selected from personal information, demographic information, medical information, biomarker information, drug intake and medication regimens, geographic information, environmental information, lifestyle information, health and well-being, biometric information, behavioral information, digital intervention-related data, goal setting, medical considerations, health and well-being, preferences, availability, time constraints, scheduling, individual strengths and weaknesses, cultural considerations, communication channel preferences, feedback from the individual, feedback from healthcare providers, or a combination thereof.

[0044] In one embodiment, the method further includes analyzing data by machine learning, artificial intelligence (AI), statistical modeling, or a combination thereof, in order to adapt the digital therapeutic intervention plan. In one embodiment, the analysis determines the degree of improvement to be achieved by the individual implementing the digital therapeutic intervention plan. In one embodiment, the method further includes providing instructions to the individual before, during, and / or after any stage of the digital therapeutic intervention plan.

[0045] In one embodiment, at least one psychological intervention is selected from guided imaging, psychoeducation, psychotherapy, cognitive behavioral therapy, stress and anxiety management training, mindfulness-based interventions, body scanning training, sleep hygiene, fatigue training, Acceptance and Commitment Therapy (ACT), Dialectical Behavior Therapy (DBT), psychodynamic therapy, Solution-Focused Brief Therapy (SFBT), narrative therapy, pain therapy, addiction therapy, Gestalt therapy, behavioral activation therapy, telepsychiatry and teletherapy, or a combination thereof.

[0046] In one embodiment, at least one cognitive intervention is selected from maze navigation, spatial navigation, Magic 7 training, memory enhancement techniques, attention training, problem solving, sonification exercises, data visualization, geometric puzzles, shape and pattern matching, visual cognitive tasks, spatial reasoning games, face detection training, drawing games, concentration training, reading comprehension training, or any combination thereof.

[0047] In one embodiment, at least one physical intervention is selected from physiotherapy, voice therapy, speech therapy, swallowing therapy, breathing training, saliva and drooling therapy, chewing therapy, facial expression training, tremor management, mobility training, freeze and stiffness exercises, tapping training, limb agility exercises, volume-sustain-pitch training, training for gait freeze, motor function therapy, dance therapy, handwriting training, balance exercises, postural stability training, muscle training, stretching exercises, coordination training, metronome training, fine motor skills training, or a combination thereof.

[0048] In one embodiment, the maze is selected from a Hebb-Williams maze, a Morris water maze, a Burns maze, a radial arm maze, a T-maze, and an elevated plus maze. In one embodiment, sensory inhibition includes at least partial inhibition of at least one sensory modal input. In one embodiment, at least one sensory modal input is selected from visual, auditory, and tactile. In one embodiment, sensory substitution includes at least partial substitution of at least one sensory modal input with at least one other sensory modal input.

[0049] In one embodiment, at least partial substitution of at least one sensory modality input by at least one other sensory modality input is From sight to hearing and / or touch, From hearing to sight and / or touch, The sense of touch is selected from sight and / or hearing.

[0050] In one embodiment, sensory integration includes at least a partial combination of at least two sensory modal inputs. In one embodiment, the at least two sensory modal inputs are selected from visual, auditory, and tactile. In one embodiment, the digital intervention includes the individual interacting with a personal electronic device using any of the following means selected from touch gestures, motion gestures, voice commands, text input, camera and media interaction, sensor-based interaction, or a combination thereof.

[0051] In one embodiment, touch gestures are selected from tapping, swiping, scrolling, pinching, dragging, double tapping, or a combination thereof. In one embodiment, motion gestures are selected from tilting, shaking, rotating, body movements, weaving, or a combination thereof. In one embodiment, camera and / or media interaction is selected from taking photographs, recording videos, uploading / downloading images, uploading / downloading audio, uploading / downloading videos, augmented reality, or a combination thereof. In one embodiment, sensor-based interaction is performed by a global positioning system (GPS) system, accelerometer, gyroscope, proximity sensor, or a combination thereof. In one embodiment, at least one digital intervention is performed in the form of an instructional video, an interactive video including input and feedback from an individual, a game, an instructional prompt, a question-and-answer survey with feedback, virtual reality, augmented reality, or a combination thereof. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, extends over a period ranging from 1 second to 60 minutes. In one embodiment, the digital therapeutic intervention plan is implemented over a period ranging from 1 day to 10 years.

[0052] In one embodiment, the method further includes an adaptation plan during the process of a digital therapeutic intervention plan, and the method Receiving data and, Receiving updated data in accordance with at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, Analyzing data and updated data using machine learning, artificial intelligence (AI), or statistical modeling, This includes generating updated digital therapeutic intervention plans for individuals based on the analysis of updated data.

[0053] In one embodiment, the adaptation includes changes in any of the following, selected from: the type of intervention, the order of interventions, the frequency of interventions, the intensity of interventions, the length of interventions, the difficulty of interventions, the sensory modal inputs used, the level of interaction, or a combination thereof.

[0054] In one embodiment, the method further includes at least one additional device selected from a health monitoring system, medical device, haptic device, external speaker, headphones, virtual reality set, augmented reality glasses / device, biofeedback sensor, wearable activity tracker, smartphone, personal computing device, smart speaker, voice assistant, motion tracking sensor, virtual assistant system, internet hub, or a combination thereof, wherein the at least one additional device is configured to transfer data between a person, a personal electronic device, or a combination thereof.

[0055] In one embodiment, the health monitoring system is selected from wearable fitness trackers, remote patient monitoring (RPM) systems, telemedicine platforms, smart health devices, health and wellness apps, and hospital information systems (HIS).

[0056] In one embodiment, at least one additional device is configured to provide at least one of the following: real-time feedback to the individual based on collected data and interactions, measurement of health parameters, outputting signals to the individual, real-time customization of digital therapeutic intervention plans, monitoring the individual's engagement with and adherence to therapeutic protocols, remote monitoring, inter-device cloud synchronization and data sharing, or a combination thereof.

[0057] In one embodiment, a personal electronic device, at least one additional device, or a combination thereof, is configured to provide a sensory modal input for performing sensory inhibition, sensory substitution, sensory integration, or a combination thereof.

[0058] In one embodiment, the method is for treating, preventing, or alleviating symptoms in an individual suffering from a neurodegenerative disease. In one embodiment, the method is for use in treating, preventing, or alleviating symptoms in an individual suffering from a neurodegenerative disease.

[0059] In one embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, chronic traumatic encephalopathy (CTE), Lewy body dementia (LBD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), Huntington's disease, Creutzfeldt-Jakob disease, and Wilson's disease.

[0060] In one embodiment, the method is for treating, preventing, or alleviating symptoms in an individual suffering from a neurological disorder. In one embodiment, the method is for use in treating, preventing, or alleviating symptoms in an individual suffering from a neurological disorder.

[0061] In one embodiment, the neurological disorder is selected from mild cognitive impairment (MCI), sleep disorders, migraines and headache disorders, neuropathy, epilepsy, traumatic brain injury, spinal cord injury, and cerebrovascular disease.

[0062] In one embodiment, the method is for treating, preventing, or alleviating symptoms in an individual suffering from a psychological disorder. In one embodiment, the method is for use in treating, preventing, or alleviating symptoms in an individual suffering from a psychological disorder.

[0063] In one embodiment, the psychological disorder is selected from depression, anxiety, bipolar disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), attention-deficit / hyperactivity disorder (ADHD), eating disorders, substance use disorders, sleep disorders, autism spectrum disorder (ASD), personality disorders, schizophrenia, and dissociative disorders.

[0064] In one embodiment, non-digital medical interventions are selected from pharmaceuticals, medical procedures, physiotherapy, psychotherapy, psychiatry, rehabilitation, lifestyle interventions, nutritional supplements, mineral supplements, and physical exercise.

[0065] In one embodiment, the pharmaceutical agent is selected from dopaminergic agonists, anti-amyloid beta antibodies, opioids, immune checkpoint inhibitors, NMDA receptor antagonists, triptans, acetylcholinesterase inhibitors, neurosteroids, anti-inflammatory agents, neuroprotective agents, mitochondrial support agents, metabolic therapies, hormone therapies, tau-targeted therapies, beta-secretase inhibitors, gamma-secretase modulators, or combinations thereof.

[0066] In one embodiment, the dopaminergic agonist is selected from dopamine precursors, dopamine agonists, monoamine oxidase inhibitors (MAOIs), or combinations thereof. In one embodiment, the dopamine precursor is selected from levodopa, levodopa-carbidopa, levodopa-benserazide, levodopa-carbidopa-entacapone, foslevodopa-foscarbidopa, or combinations thereof. In one embodiment, the dopamine agonist is selected from pramipexole, ropinirole, rotigotine, apomorphine, bromocriptine, cabergoline, pergolide, rislid, or combinations thereof. In one embodiment, the monoamine oxidase inhibitor is selected from selegiline, rasagiline, safinamide, or combinations thereof. In one embodiment, the anti-amyloid-beta antibody is selected from lecabemab, aducanumab, solanezumab, gantenerumab, crenezumab, donanemab, or a combination thereof. In one embodiment, the opioid is selected from morphine, fentanyl, oxycodone, hydrocodone, buprenorphine, codeine, hydromorphone, meperidine, tapentadol, butorphanol, pethidine, levorphanol, methadone, dextropropoxifen, tramadol, ketobemidone, or a combination thereof. In one embodiment, the immune checkpoint inhibitor is selected from PD-1 inhibitors, pembrolizumab, nivolumab, cemiprimab, PD-L1 inhibitors, avelumab, atezolizumab, durvalumab, CTLA-4 inhibitors, ipilimumab, tremelimumab, LAG-3 inhibitors, leratrimab, TIM-3 inhibitors, sabatrimab, TIGIT inhibitors, tiragolumab, domvanarimab, CD40 agonists, sericrelumab, OX40 agonists, utomirumab, GITR agonists, tiragolumab, IDO1 inhibitors, VISTA inhibitors, B7-H3 inhibitors, or combinations thereof. In one embodiment, the NMDA receptor antagonist is selected from SAGE-718, memantine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N2O), ketamine, or a combination thereof.In one embodiment, the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine, galantamine, or a combination thereof. In one embodiment, the neurosteroid is selected from allopregnanolone, dehydroepiandrosterone, pregnenolone, progesterone, androstenediol, estradiol, testosterone, or a combination thereof. In one embodiment, the anti-inflammatory agent is selected from nonsteroidal anti-inflammatory drugs (NTHEs), corticosteroids, biological agents, or a combination thereof. In one embodiment, the anti-inflammatory agent is selected from ibuprofen, naproxen, aspirin, celecoxib, diclofenac, prednisone, hydrocortisone, dexamethasone, prednisolone, methylprednisolone, tumor necrosis factor (TNF) inhibitors, interleukin (IL) inhibitors, Janus kinase (JAK) inhibitors, interleukin-1 (IL-1) receptor antagonists, interleukin-6 (IL-6) inhibitors, interleukin-17 (IL-17) inhibitors, disease-modifying antirheumatic drugs (DMARDs), colchicine, or a combination thereof. In one embodiment, the neuroprotective agent is selected from allopregnanolone, dehydroepiandrosterone, pregnenolone, progesterone, androstenediol, estradiol, testosterone, ketamine, riluzole, antioxidants, vitamin E, vitamin C, alpha-lipoic acid, omega-3 fatty acids, coenzyme Q10 (CoQ10), ginkgo biloba extract, melatonin, resveratrol, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glutathione, magnesium, L-carnitine, carnosine, N-acetylcysteine ​​(NAC), curcumin, quercetin, green tea extract, bacopa monnieri, ginseng, huperzine A, or a combination thereof.In one embodiment, the nutritional supplement is selected from vitamin B, vitamin B12, omega-3 fatty acids, magnesium, zinc, iron, folic acid, vitamin C, vitamin E, probiotics, ginkgo biloba, curcumin, coenzyme Q10, acetyl-L-carnitine, alpha-lipoic acid, phosphatidylserine, bacopa monnieri, ashwagandha, rhodiola rosea, L-theanine, melatonin, or a combination thereof.

[0067] In one embodiment, the pharmaceutical agent is administered by injection, oral, topical, inhalation, transdermal, nasal, intravenous, intramuscular, subcutaneous, or a combination thereof. In one embodiment, the method is configured such that the digital therapeutic intervention plan takes into account the individual's medication intake, dosing regimen, and non-digital medical intervention schedule, and is further configured to achieve increased neural connectivity.

[0068] In one embodiment, the pharmaceutical agent is administered with a conditioned stimulus selected from visual, auditory, tactile, or a combination thereof. In one embodiment, at least one digital intervention, a pharmaceutical agent, or a combination thereof is administered with a conditioned stimulus selected from visual, auditory, tactile, or a combination thereof. Other examples of conditioned stimuli include, but are not limited to, olfaction and gustatory senses.

[0069] In one embodiment, the method disclosed herein further includes gamification elements. In one embodiment, the gamification elements are selected from badges, scores, leaderboards, rankings, game currency, quests or missions, characters or avatars, virtual goods, social media features, experience points (XP), or a combination thereof.

[0070] In one embodiment, the present invention provides a method for improving immune function in an individual, and this method is This includes individuals performing at least one digital intervention from among sensory inhibition, sensory substitution, sensory integration, or a combination thereof.

[0071] In one embodiment, at least one digital intervention is included within a digital therapeutic intervention plan. In one embodiment, the digital intervention includes at least one psychological intervention, at least one cognitive intervention, or a combination thereof. In one embodiment, at least one digital intervention is performed at least partially on a personal electronic device. In one embodiment, the method further includes transferring data for an individual, wherein the data is selected from personal information, demographic information, medical information, biomarker information, drug intake and medication regimens, geographic information, environmental information, lifestyle information, health and well-being, biometric information, behavioral information, digital intervention-related data, goal setting, medical considerations, health and well-being, preferences, availability, time constraints, scheduling, individual strengths and weaknesses, cultural considerations, communication channel preferences, feedback from the individual, feedback from healthcare providers, or a combination thereof.

[0072] In one embodiment, the method further includes analyzing data by machine learning, artificial intelligence (AI), statistical modeling, or a combination thereof, in order to adapt the digital therapeutic intervention plan. In one embodiment, the analysis determines the degree of improvement achieved by the individual implementing the digital therapeutic intervention plan. In one embodiment, the method further includes providing instructions to the individual before, during, and / or after any stage of the digital therapeutic intervention plan. In one embodiment, at least one psychological intervention is selected from guided imaging, psychoeducation, psychotherapy, cognitive behavioral therapy, stress and anxiety management training, mindfulness-based intervention, body scanning training, sleep hygiene, fatigue training, acceptance and commitment therapy (ACT), dialectical behavior therapy (DBT), psychodynamic therapy, solution-focused brief therapy (SFBT), narrative therapy, pain therapy, addiction therapy, gestalt therapy, behavioral activation therapy, telepsychiatry and teletherapy, or a combination thereof.

[0073] In one embodiment, at least one cognitive intervention is selected from maze navigation, spatial navigation, Magic 7 training, memory enhancement techniques, attention training, problem solving, sonification exercises, data visualization, geometric puzzles, shape and pattern matching, visual cognitive tasks, spatial reasoning games, face detection training, drawing games, concentration training, reading comprehension training, or any combination thereof.

[0074] In one embodiment, the maze is selected from a Hebb-Williams maze, a Morris water maze, a Burns maze, a radial arm maze, a T-maze, and an elevated plus maze. In one embodiment, sensory inhibition includes at least a partial reduction of at least one sensory modal input. In one embodiment, at least one sensory modal input is selected from visual, auditory, and tactile. In one embodiment, sensory substitution includes at least a partial substitution of at least one sensory modal input with at least one other sensory modal input. In one embodiment, at least a partial substitution of at least one sensory modal input with at least one other sensory modal input is From sight to hearing and / or touch, From hearing to sight and / or touch, The sense of touch is selected from sight and / or hearing.

[0075] In one embodiment, sensory integration includes at least a partial combination of at least two sensory modal inputs. In one embodiment, the at least two sensory modal inputs are selected from visual, auditory, and tactile. In one embodiment, the digital intervention includes the individual interacting with a personal electronic device using any of the following means selected from touch gestures, motion gestures, voice commands, text input, camera and media interaction, sensor-based interaction, or a combination thereof. In one embodiment, the touch gestures are selected from tapping, swiping, scrolling, pinching, dragging, double tapping, or a combination thereof.

[0076] In one embodiment, motion gestures are selected from tilting, shaking, rotating, body movements, waving, or a combination thereof. In one embodiment, camera and / or media interaction is selected from taking photographs, recording videos, uploading / downloading images, uploading / downloading audio, uploading / downloading videos, augmented reality, or a combination thereof. In one embodiment, sensor-based interaction is performed by a Global Positioning System (GPS) system, accelerometer, gyroscope, proximity sensor, or a combination thereof. In one embodiment, at least one digital intervention is performed in the form of instructional video, interactive video including input and feedback from the individual, games, instructional prompts, question-and-answer surveys with feedback, virtual reality, augmented reality, or a combination thereof. In one embodiment, at least one psychological intervention, at least one cognitive intervention, or a combination thereof, spans a period ranging from 1 second to 60 minutes. In one embodiment, the digital therapeutic intervention plan is executed over a period ranging from 1 day to 10 years.

[0077] In one embodiment, the method further includes an adaptation plan during the process of a digital therapeutic intervention plan, and the method Receiving data and, Receiving updated data in accordance with at least one psychological intervention, at least one cognitive intervention, or a combination thereof, Analyzing data and updated data using machine learning, artificial intelligence (AI), or statistical modeling, This includes generating updated digital therapeutic intervention plans for individuals based on the analysis of updated data.

[0078] In one embodiment, the adaptation includes changes in any of the following, selected from: the type of intervention, the order of interventions, the frequency of interventions, the intensity of interventions, the length of interventions, the difficulty of interventions, the sensory modal inputs used, the level of interaction, or a combination thereof.

[0079] In one embodiment, the method further includes at least one additional device selected from a health monitoring system, medical device, haptic device, external speaker, headphones, virtual reality set, augmented reality glasses / device, biofeedback sensor, wearable activity tracker, smartphone, personal computing device, smart speaker, voice assistant, motion tracking sensor, virtual assistant system, internet hub, or a combination thereof, wherein the at least one additional device is configured to transfer data between a person, a personal electronic device, or a combination thereof.

[0080] In one embodiment, at least one additional device is configured to provide at least one of the following: real-time feedback to the individual based on collected data and interactions, measurement of health parameters, outputting signals to the individual, real-time customization of digital therapeutic intervention plans, monitoring the individual's engagement with and adherence to therapeutic protocols, remote monitoring, inter-device cloud synchronization and data sharing, or a combination thereof.

[0081] In one embodiment, the health monitoring system is selected from wearable fitness trackers, remote patient monitoring (RPM) systems, telemedicine platforms, smart health devices, health and wellness apps, and hospital information systems (HIS). In one embodiment, a personal electronic device, at least one additional device, or a combination thereof, is configured to provide sensory modal input for performing sensory suppression, sensory substitution, sensory integration, or a combination thereof.

[0082] In one embodiment, the method is for treating, preventing, or alleviating symptoms in an individual suffering from an immune-related disorder.

[0083] In one embodiment, the immune-related disorder is selected from autoimmune disorders and immunodeficiency disorders.

[0084] In one embodiment, autoimmune disorders include alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, autoimmune urticaria, bullous pemphigoid, scarring pemphigoid, herpetiform dermatitis, dermatomyositis, discoid lupus erythematosus, acquired epidermolysis bullosa, pemphigoid of pregnancy, hidradenitis suppurativa, lichen planus, lichen sclerosing, linear IgA disease, focal scleroderma, psoriasis, pemphigus vulgaris, systemic scleroderma, vitiligo, autoimmune enteropathy, autoimmune hepatitis, celiac disease, Crohn's disease, pernicious anemia, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, rheumatic heart disease, and river disease. Sakisaki disease, giant cell arteritis, Takayasu's arteritis, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), leukocytoclastic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, Goodpasture syndrome, IgA nephropathy, membranous nephropathy, lupus nephritis, primary sclerosing cholangitis, acute disseminated encephalomyelitis, acute motor axonal neuropathy, anti-NMDA receptor encephalitis, autoimmune encephalitis, Lowe concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, myasthenia gravis, neuromyelitis optica / NMOSD, rigid man syndrome, Sydenham's chorea, undifferentiated connective tissue disease (UCTD), Addison's disease, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune polyganocytosis type 1 (APS1), autoimmune polyganocytosis type 2 (APS2), autoimmune polyganocytosis type 3 (APS3), type 1 diabetes mellitus. The following conditions are selected: Graves' disease, Hashimoto's thyroiditis, Aud's thyroiditis, Sjögren's syndrome, rheumatoid pulmonary disease, sarcoidosis, autoimmune hemolytic anemia, immune thrombocytopenia, thrombotic thrombocytopenic purpura, antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria, autoimmune retinopathy, autoimmune uveitis, Cogan's syndrome, Graves' ophthalmopathy, Mohren's ulcer, opsoclonus-myoclonus syndrome, optic neuritis, Susack's syndrome, sympathetic ophthalmitis, inclusion body myositis, myositis, autoimmune neuromyotonia, paraneoplastic cerebellar degeneration, and polymyositis.

[0085] In one embodiment, the immunodeficiency disorder is selected from severe combined immunodeficiency (SCID), DiGeorge syndrome, hyperimmunoglobulin E syndrome (Job's syndrome), common variant immunodeficiency (CVID), chronic granulomatous disease (CGD), Wiskott-Aldrich syndrome (WAS), autoimmune lymphoproliferative syndrome (ALPS), hyper-IgM syndrome, leukocyte adhesion disorder (LAD), NF-κB essential modifier (NEMO) mutation, selective immunoglobulin A deficiency, X-linked agammaglobulinemia (XLA), X-linked lymphoproliferative disorder (XLP), and ataxia telangiectasia.

[0086] In one embodiment, the method is intended to treat, prevent, or alleviate symptoms in individuals suffering from Parkinson's disease, Alzheimer's disease, or mild cognitive impairment (MCI).

[0087] In one embodiment, the present invention provides a method for improving immune function in an individual, and this method is Individuals performing at least one digital intervention from sensory inhibition, sensory substitution, sensory integration, or a combination thereof, This includes administering at least one non-digital medical intervention before, during, or after at least one digital intervention, or a combination thereof.

[0088] In one embodiment, at least one digital intervention is included within the digital therapeutic intervention plan.

[0089] In one embodiment, the digital intervention includes at least one psychological intervention, at least one cognitive intervention, or a combination thereof.

[0090] In one embodiment, at least one digital intervention is performed, at least partially, on a personal electronic device.

[0091] In one embodiment, the method further includes transferring data for an individual, wherein the data is selected from personal information, demographic information, medical information, biomarker information, drug intake and medication regimens, geographic information, environmental information, lifestyle information, health and well-being, biometric information, behavioral information, digital intervention-related data, goal setting, medical considerations, health and well-being, preferences, availability, time constraints, scheduling, individual strengths and weaknesses, cultural considerations, communication channel preferences, feedback from the individual, feedback from healthcare providers, or a combination thereof.

[0092] In one embodiment, the method further includes analyzing data by machine learning, artificial intelligence (AI), statistical modeling, or a combination thereof, in order to adapt a digital therapeutic intervention plan.

[0093] In one embodiment, the degree of improvement achieved by an individual implementing a digital therapeutic intervention plan is determined by analysis.

[0094] In one embodiment, the method further includes providing instructions to an individual before, during, and / or after any stage of a digital therapeutic intervention plan.

[0095] In one embodiment, at least one psychological intervention is selected from guided imaging, psychoeducation, psychotherapy, cognitive behavioral therapy, stress and anxiety management training, mindfulness-based interventions, body scanning training, sleep hygiene, fatigue training, Acceptance and Commitment Therapy (ACT), Dialectical Behavior Therapy (DBT), psychodynamic therapy, Solution-Focused Brief Therapy (SFBT), narrative therapy, pain therapy, addiction therapy, Gestalt therapy, behavioral activation therapy, telepsychiatry and teletherapy, or a combination thereof.

[0096] In one embodiment, at least one cognitive intervention is selected from maze navigation, spatial navigation, Magic 7 training, memory enhancement techniques, attention training, problem solving, sonification exercises, data visualization, geometric puzzles, shape and pattern matching, visual cognitive tasks, spatial reasoning games, face detection training, drawing games, concentration training, reading comprehension training, or any combination thereof.

[0097] In one embodiment, the maze is selected from Hebb-Williams mazes, Morris water mazes, Barnes mazes, radial arm mazes, T-mazes, and elevated plus mazes.

[0098] In one embodiment, sensory inhibition includes at least a partial reduction of at least one sensory modal input.

[0099] In one embodiment, at least one sensory modal input is selected from visual, auditory, and tactile.

[0100] In one embodiment, sensory substitution includes at least partial substitution of at least one sensory modality input with at least one other sensory modality input.

[0101] In one embodiment, at least partial substitution of at least one sensory modality input by at least one other sensory modality input is From sight to hearing and / or touch, From hearing to sight and / or touch, The sense of touch is selected from sight and / or hearing.

[0102] In one embodiment, sensory integration includes at least a partial combination of at least two sensory modal inputs.

[0103] In one embodiment, at least two sensory modal inputs are selected from visual, auditory, and tactile.

[0104] In one embodiment, the digital intervention includes the individual interacting with a personal electronic device using any of the following means selected from touch gestures, motion gestures, voice commands, text input, camera and media interaction, sensor-based interaction, or a combination thereof.

[0105] In one embodiment, the touch gesture is selected from tapping, swiping, scrolling, pinching, dragging, double-tapping, or a combination thereof.

[0106] In one embodiment, the motion gesture is selected from tilting, shaking, rotating, body movement, waving, or a combination thereof.

[0107] In one embodiment, the camera and / or media interaction may be selected from taking a photograph, recording a video, uploading / downloading an image, uploading / downloading audio, uploading / downloading a video, augmented reality, or a combination thereof.

[0108] In one embodiment, sensor-based interaction is performed by a global positioning system (GPS) system, an accelerometer, a gyroscope, a proximity sensor, or a combination thereof, selected from the above.

[0109] In one embodiment, at least one digital intervention is carried out in the form of an instructional video, an interactive video including input and feedback from an individual, a game, an instructional prompt, a question-and-answer survey with feedback, virtual reality, augmented reality, or a combination thereof.

[0110] In one embodiment, at least one psychological intervention, at least one cognitive intervention, or a combination thereof, extends for a period ranging from 1 second to 60 minutes.

[0111] In one embodiment, the digital therapeutic intervention plan is implemented over a period ranging from one day to ten years.

[0112] In one embodiment, the method further includes an adaptation plan during the process of a digital therapeutic intervention plan, and the method Receiving data and, Receiving updated data in accordance with at least one psychological intervention, at least one cognitive intervention, or a combination thereof, Analyzing data and updated data using machine learning, artificial intelligence (AI), or statistical modeling, This includes generating updated digital therapeutic intervention plans for individuals based on the analysis of updated data.

[0113] In one embodiment, the adaptation includes changes in any of the following, selected from: the type of intervention, the order of interventions, the frequency of interventions, the intensity of interventions, the length of interventions, the difficulty of interventions, the sensory modal inputs used, the level of interaction, or a combination thereof.

[0114] In one embodiment, the method further includes at least one additional device selected from a health monitoring system, medical device, haptic device, external speaker, headphones, virtual reality set, augmented reality glasses / device, biofeedback sensor, wearable activity tracker, smartphone, personal computing device, smart speaker, voice assistant, motion tracking sensor, virtual assistant system, internet hub, or a combination thereof, wherein the at least one additional device is configured to transfer data between a person, a personal electronic device, or a combination thereof.

[0115] In one embodiment, at least one additional device is configured to provide at least one of the following: real-time feedback to the individual based on collected data and interactions, measurement of health parameters, outputting signals to the individual, real-time customization of digital therapeutic intervention plans, monitoring the individual's engagement with and adherence to therapeutic protocols, remote monitoring, inter-device cloud synchronization and data sharing, or a combination thereof.

[0116] In one embodiment, the health monitoring system is selected from wearable fitness trackers, remote patient monitoring (RPM) systems, telemedicine platforms, smart health devices, health and wellness apps, and hospital information systems (HIS).

[0117] In one embodiment, a personal electronic device, at least one additional device, or a combination thereof, is configured to provide a sensory modal input for performing sensory inhibition, sensory substitution, sensory integration, or a combination thereof.

[0118] In one embodiment, the method is for treating, preventing, or alleviating symptoms in an individual suffering from an immune-related disorder.

[0119] In one embodiment, the immune-related disorder is selected from autoimmune disorders and immunodeficiency disorders.

[0120] In one embodiment, autoimmune disorders include alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, autoimmune urticaria, bullous pemphigoid, scarring pemphigoid, herpetiform dermatitis, dermatomyositis, discoid lupus erythematosus, acquired epidermolysis bullosa, pemphigoid of pregnancy, hidradenitis suppurativa, lichen planus, lichen sclerosing, linear IgA disease, focal scleroderma, psoriasis, pemphigus vulgaris, systemic scleroderma, vitiligo, autoimmune enteropathy, autoimmune hepatitis, celiac disease, Crohn's disease, pernicious anemia, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, rheumatic heart disease, and river disease. Sakisaki disease, giant cell arteritis, Takayasu's arteritis, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), leukocytoclastic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, Goodpasture syndrome, IgA nephropathy, membranous nephropathy, lupus nephritis, primary sclerosing cholangitis, acute disseminated encephalomyelitis, acute motor axonal neuropathy, anti-NMDA receptor encephalitis, autoimmune encephalitis, Lowe concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, myasthenia gravis, neuromyelitis optica / NMOSD, rigid man syndrome, Sydenham's chorea, undifferentiated connective tissue disease (UCTD), Addison's disease, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune polyganocytosis type 1 (APS1), autoimmune polyganocytosis type 2 (APS2), autoimmune polyganocytosis type 3 (APS3), type 1 diabetes mellitus. The following conditions are selected: Graves' disease, Hashimoto's thyroiditis, Aud's thyroiditis, Sjögren's syndrome, rheumatoid pulmonary disease, sarcoidosis, autoimmune hemolytic anemia, immune thrombocytopenia, thrombotic thrombocytopenic purpura, antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria, autoimmune retinopathy, autoimmune uveitis, Cogan's syndrome, Graves' ophthalmopathy, Mohren's ulcer, opsoclonus-myoclonus syndrome, optic neuritis, Susack's syndrome, sympathetic ophthalmitis, inclusion body myositis, myositis, autoimmune neuromyotonia, paraneoplastic cerebellar degeneration, and polymyositis.

[0121] In one embodiment, the immunodeficiency disorder is selected from severe combined immunodeficiency (SCID), DiGeorge syndrome, hyperimmunoglobulin E syndrome (Job's syndrome), common variant immunodeficiency (CVID), chronic granulomatous disease (CGD), Wiskott-Aldrich syndrome (WAS), autoimmune lymphoproliferative syndrome (ALPS), hyper-IgM syndrome, leukocyte adhesion disorder (LAD), NF-κB essential modifier (NEMO) mutation, selective immunoglobulin A deficiency, X-linked agammaglobulinemia (XLA), X-linked lymphoproliferative disorder (XLP), and ataxia telangiectasia.

[0122] In one embodiment, non-digital medical interventions are selected from pharmaceuticals, medical procedures, physiotherapy, psychotherapy, psychiatry, rehabilitation, lifestyle interventions, nutritional supplements, mineral supplements, and physical exercise.

[0123] In one embodiment, the pharmaceutical agent is selected from immunosuppressants, bioimmunotherapies, psychedelic drugs, and immune checkpoint inhibitors.

[0124] The method according to claim 37, wherein the immunosuppressant is selected from steroids, colchicine, hydroxychloroquine, sulfasalazine, dapsone, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, or a combination thereof.

[0125] In one embodiment, the biological immunotherapy is selected from anakinra, canakinumab, rilonacept, infliximab, adalimumab, golimumab, etanercept, certolizumab, tocilizumab, sarilumab, eculizumab, rituximab, belimumab, abatacept, secukinumab, ixekizumab, brodalumab, guzerkumab, ustekinumab, dupixent, vedolizumab, tofacitinib, upadacitinib, baricitinib, mepolizumab, rezlizumab, benralizumab, or a combination thereof.

[0126] In one embodiment, the immune checkpoint inhibitor is selected from PD-1 inhibitors, pembrolizumab, nivolumab, cemiprimab, PD-L1 inhibitors, avelumab, atezolizumab, durvalumab, CTLA-4 inhibitors, ipilimumab, tremelimumab, LAG-3 inhibitors, leratrimab, TIM-3 inhibitors, sabatrimab, TIGIT inhibitors, tiragolumab, domvanarimab, CD40 agonists, sericrelumab, OX40 agonists, utomirumab, GITR agonists, tiragolumab, IDO1 inhibitors, VISTA inhibitors, B7-H3 inhibitors, or combinations thereof.

[0127] In one embodiment, the pharmaceutical agent is administered by injection, oral, topical, inhalation, transdermal, nasal, intravenous, intramuscular, subcutaneous, or a combination thereof.

[0128] In one embodiment, the method is further configured so that the digital therapeutic intervention plan takes into account the individual's medication intake, drug regimen, and non-digital medical intervention schedule in order to achieve improved immune function.

[0129] In one embodiment, the pharmaceutical agent is administered with a conditioned stimulus selected from visual, auditory, tactile, or a combination thereof.

[0130] In one embodiment, the method is intended to treat, prevent, or alleviate symptoms in individuals suffering from Parkinson's disease, Alzheimer's disease, or mild cognitive impairment (MCI).

[0131] In one embodiment, the present invention provides a method for improving motor skills in an individual, and this method is This includes an individual performing at least one digital intervention, which may involve a physical intervention based on sensory inhibition, sensory substitution, sensory integration, or a combination thereof.

[0132] In one embodiment, at least one digital intervention is included in the digital therapeutic intervention plan. In one embodiment, at least one digital intervention is performed at least partially on a personal electronic device.

[0133] In one embodiment, the method further includes transferring data for an individual, wherein the data is selected from personal information, demographic information, medical information, biomarker information, drug intake and medication regimens, geographic information, environmental information, lifestyle information, health and well-being, biometric information, behavioral information, digital intervention-related data, goal setting, medical considerations, health and well-being, preferences, availability, time constraints, scheduling, individual strengths and weaknesses, cultural considerations, communication channel preferences, feedback from the individual, feedback from healthcare providers, or a combination thereof.

[0134] In one embodiment, the method further includes analyzing data by machine learning, artificial intelligence (AI), statistical modeling, or a combination thereof, in order to adapt the digital therapeutic intervention plan. In one embodiment, the analysis determines the degree of improvement to be achieved by the individual implementing the digital therapeutic intervention plan. In one embodiment, the method further includes providing instructions to the individual before, during, and / or after any stage of the digital therapeutic intervention plan.

[0135] In one embodiment, at least one physical intervention is selected from physiotherapy, voice therapy, speech therapy, swallowing therapy, breathing training, saliva and drooling therapy, chewing therapy, facial expression training, tremor management, mobility training, freeze and stiffness exercises, tapping training, limb agility exercises, volume-sustain-pitch training, training for gait freeze, motor function therapy, handwriting training, balance exercises, dance therapy, postural stability training, muscle strength training, stretching exercises, coordination training, gross motor skills training, metronome training, fine motor skills training, or a combination thereof.

[0136] In one embodiment, sensory inhibition includes at least partial inhibition of at least one sensory modal input. In one embodiment, the at least one sensory modal input is selected from visual, auditory, and tactile. In one embodiment, sensory substitution includes at least partial substitution of at least one sensory modal input with at least one other sensory modal input.

[0137] In one embodiment, at least partial substitution of at least one sensory modality input by at least one other sensory modality input is From sight to hearing and / or touch, From hearing to sight and / or touch, The sense of touch is selected from sight and / or hearing.

[0138] In one embodiment, sensory integration includes at least a partial combination of at least two sensory modal inputs. In one embodiment, the at least two sensory modal inputs are selected from visual, auditory, and tactile. In one embodiment, at least one digital intervention includes the individual interacting with a personal electronic device using any of the following means selected from touch gestures, motion gestures, voice commands, text input, camera and media interaction, sensor-based interaction, or a combination thereof. In one embodiment, touch gestures are selected from tapping, swiping, scrolling, pinching, dragging, double tapping, or a combination thereof. In one embodiment, motion gestures are selected from tilting, shaking, rotating, body movements, weaving, or a combination thereof. In one embodiment, camera and media interaction is selected from taking photographs, recording videos, uploading / downloading images, uploading / downloading audio, augmented reality, or a combination thereof. In one embodiment, sensor-based interaction is performed on a personal electronic device by a global positioning system (GPS) system, an accelerometer, a gyroscope, a proximity sensor, or a combination thereof.

[0139] In one embodiment, at least one digital intervention is carried out in the form of an instructional video, an interactive video including input and feedback from an individual, a game, an instructional prompt, a question-and-answer survey with feedback, virtual reality, augmented reality, or a combination thereof. In one embodiment, at least one digital intervention spans a period ranging from 1 second to 60 minutes. In one embodiment, the digital therapeutic intervention plan is implemented over a period ranging from 1 day to 10 years.

[0140] In one embodiment, the method further includes an adaptation plan during the process of a digital therapeutic intervention plan, and the method Receiving data and, Receiving updated data in response to at least one digital intervention, Analyzing data and updated data using machine learning, artificial intelligence (AI), or statistical modeling, This includes generating updated digital therapeutic intervention plans for individuals based on the analysis of updated data.

[0141] In one embodiment, the adaptation includes changes in any of the following, selected from: the type of intervention, the order of interventions, the frequency of interventions, the intensity of interventions, the length of interventions, the difficulty of interventions, the sensory modal inputs used, the level of interaction, or a combination thereof.

[0142] In one embodiment, the method further includes at least one additional device selected from a health monitoring system, medical device, haptic device, external speaker, headphones, virtual reality set, augmented reality glasses / device, biofeedback sensor, wearable activity tracker, smartphone, personal computing device, smart speaker, voice assistant, motion tracking sensor, virtual assistant system, internet hub, or a combination thereof, wherein the at least one additional device is configured to transfer data between a person, a personal electronic device, or a combination thereof.

[0143] In one embodiment, at least one additional device is configured to provide at least one of the following: real-time feedback to the individual based on collected data and interactions, measurement of health parameters, outputting signals to the individual, real-time customization of digital therapeutic intervention plans, monitoring the individual's engagement with and adherence to therapeutic protocols, remote monitoring, inter-device cloud synchronization and data sharing, or a combination thereof.

[0144] In one embodiment, the health monitoring system is selected from wearable fitness trackers, remote patient monitoring (RPM) systems, telemedicine platforms, smart health devices, health and wellness apps, and hospital information systems (HIS).

[0145] In one embodiment, a personal electronic device, at least one additional device, or a combination thereof, is configured to provide a sensory modal input for performing sensory inhibition, sensory substitution, sensory integration, or a combination thereof.

[0146] In one embodiment, the method is for treating, preventing, or alleviating symptoms in an individual suffering from a motor disorder. In one embodiment, the method is for use in treating, preventing, or alleviating symptoms in an individual suffering from a motor disorder.

[0147] In one embodiment, the motor disorder is selected from parkinsonism, ataxia, dystonia, tremor, chorea, tics, spasticity, gait disturbance, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Lewy body dementia (LBD), corticobasal degeneration, Huntington's disease, Friedreich's ataxia, idiopathic tremor, myoclonus, Tourette syndrome, restless legs syndrome, tardive dyskinesia, and Wilson's disease.

[0148] In one embodiment, the present invention provides a computer implementation method for digital therapy for an individual, and this method is This includes presenting individuals with digital mazes on their personal electronic devices, Here, a personal electronic device provides sensory modal input selected from visual, auditory, tactile, or a combination thereof, enabling the individual to navigate a digital maze from a starting point to an ending point.

[0149] In one embodiment, the digital maze includes at least one obstacle selected from outer walls, inner walls, dead ends, objects, turns, interconnected paths, or a combination thereof.

[0150] In one embodiment, the sensory modal input is configured to assist the individual in completing a digital maze in the shortest time, shortest path, fewest obstacle collisions, or a combination thereof. In one embodiment, the digital maze is presented to the individual for at least one iteration. In one embodiment, the method further includes generating a performance score upon completion of each iteration of the digital maze by considering the time taken, the path taken, the number of obstacle collisions the individual had, or a combination thereof, when navigating at least one digital maze.

[0151] In one embodiment, the method further includes generating a threshold performance score for a digital maze, and if this score is exceeded, the individual is no longer presented with a digital maze to complete. In one embodiment, the method further includes a personal electronic device providing a plurality of digital mazes, where for each digital maze of the plurality, an increase in sensory substitution is presented after completion of each digital maze and / or after a threshold performance score is achieved. Here, sensory substitution includes a personal electronic device providing at least partially substitution of at least one of the sensory modal inputs with at least one of the other sensory modal inputs.

[0152] In one embodiment, the method further includes one of the sensory modal inputs, From sight to hearing and / or touch, From hearing to sight and / or touch, This includes completely replacing the input with at least one other of the sensory modal inputs selected from tactile, visual, and / or auditory inputs.

[0153] In one embodiment, a personal electronic device is configured to perform navigation by touch gestures, motion gestures, voice commands, text input, camera and media interaction, sensor-based interaction, or a combination thereof. In one embodiment, touch gestures are selected from tapping, swiping, scrolling, pinching, dragging, double tapping, or a combination thereof. In one embodiment, motion gestures are selected from tilting, shaking, rotating, body movements, weaving, or a combination thereof. In one embodiment, auditory input is selected from changes in pitch, changes in loudness, changes in tone, changes in melody, changes in rhythm, changes in music, or a combination thereof.

[0154] In one embodiment, the method further includes at least one additional device selected from a haptic device, external speaker, headphones, virtual reality set, augmented reality glasses / device, biofeedback sensor, wearable activity tracker, smartphone, personal computing device, smart speaker, voice assistant, motion tracking sensor, virtual assistant system, internet hub, or a combination thereof, wherein at least one additional device is configured to transfer data between a person, a personal electronic device, or a combination thereof.

[0155] In one embodiment, a personal electronic device, at least one additional device, or a combination thereof, is configured to provide sensory modal input. In one embodiment, the tactile cue is vibration. In one embodiment, the method further includes the personal electronic device providing, for each digital maze, a plurality of digital mazes of increasing difficulty following completion and / or achievement of a threshold performance score.

[0156] In one embodiment, the method further includes a personal electronic device providing increased sensory substitutions for each digital maze of increasing difficulty, Here, sensory substitution includes a personal electronic device providing at least partially substitution of at least one of the sensory modal inputs with at least one of the other sensory modal inputs.

[0157] In one embodiment, the method further includes one of the sensory modal inputs, From sight to hearing and / or touch, From hearing to sight and / or touch, This includes completely replacing the input with at least one other of the sensory modal inputs selected from tactile, visual, and / or auditory inputs.

[0158] In one embodiment, increasing the difficulty is achieved by randomly generating digital mazes of different structures, increasing the path length, increasing the number of turns, increasing the number of obstacles, diversifying the types of obstacles, decreasing the path width, incorporating time challenges, increasing the performance threshold score, changing the sensory modal input, adding interactive elements, incorporating distractions, incorporating tasks, incorporating moving obstacles, or a combination thereof.

[0159] In one embodiment, the digital maze includes 1 to 1,000,000,000 obstacles. In one embodiment, the obstacles are stationary, moving, or a combination thereof. In one embodiment, the method further includes providing instructions to the individual before, during, after, or a combination thereof, the digital maze. In one embodiment, the personal electronic device is selected from a smartphone, tablet, wearable device, smart TV, computer, laptop, e-reader, game console, smartwatch, fitness tracker, portable media player, digital camera, virtual reality (VR) headset, augmented reality (AR) device, portable GPS device, portable Bluetooth device, portable digital assistant, smart glasses and audio device, or any combination thereof. In one embodiment, the method is intended for use in a digital therapeutic intervention.

[0160] In one embodiment, a digital therapeutic intervention for an individual includes sensory inhibition, sensory substitution, sensory integration, or a combination thereof. In one embodiment, a digital therapy includes at least one digital therapeutic intervention, which includes sensory inhibition, sensory substitution, sensory integration, or a combination thereof. In one embodiment, sensory inhibition includes at least partial inhibition of at least one sensory modal input. In one embodiment, at least one sensory modal input is selected from visual, auditory, and tactile. In one embodiment, sensory substitution includes at least partial substitution of at least one sensory modal input with at least one other sensory modal input. In one embodiment, at least partial substitution of at least one sensory modal input with at least one other sensory modal input is From sight to hearing and / or touch, From hearing to sight and / or touch, The sense of touch is selected from sight and / or hearing.

[0161] In one embodiment, sensory integration includes at least a partial combination of at least two sensory modal inputs. In one embodiment, the at least two sensory modal inputs are selected from visual, auditory, and tactile.

[0162] In one embodiment, the present invention is A processor comprising at least one personal electronic device, wherein at least one personal electronic device includes an internal memory system, A digital therapeutic system is provided, comprising a software application for a digital therapeutic intervention that performs the computer implementation method described in claim 1.

[0163] In one embodiment, the digital therapeutic intervention includes multiple intervention sessions. In one embodiment, the system further includes digitally stored instructions for the digital therapeutic intervention. Here, at least one processor is configured to execute digitally stored instructions, thereby allowing a software application to perform functions on a personal electronic device, and the software application, Receiving user input through multiple interactive elements, To process user input and execute multiple intervention sessions, data is transferred between the internal memory system and software applications. It is further configured to display a graphical user interface (GUI) related to digital therapeutic interventions on a personal electronic device.

[0164] In one embodiment, the system further includes at least one analytical tool based on machine learning, artificial intelligence (AI), statistical modeling, or a combination thereof, and is configured to analyze data for the analysis and personalization of digital therapeutic interventions.

[0165] In one embodiment, the system further includes at least one external storage system. In one embodiment, the at least one external storage system is selected from a database, USB storage, network-attached storage (NAS), cloud server, online repository, or a combination thereof. In one embodiment, multiple interactive elements are selected from user commands, user selections, data entry, or a combination thereof. In one embodiment, the GUI is presented to the user in a format selected from text, images, video, audio, or vibration, in response to information about the user's interactions and / or software applications. In one embodiment, the GUI is configured to adapt its presentation format based on the individual's device type, accessibility settings, past user interactions, or a combination thereof.

[0166] In one embodiment, the system is further configured to perform a plurality of background tasks. In one embodiment, the plurality of background tasks are selected from maintaining application functionality, data synchronization, updates, delivery of notifications to the user, system monitoring, error logging, cache management, security checks, data encryption, or a combination thereof. In one embodiment, at least one processor is configured to onboard, transfer, analyze, or combine data selected from user interactions, user preferences, user demographics, user usage patterns, user feedback, timestamps, data from the plurality of intervention sessions, or a combination thereof. In one embodiment, the system further includes at least one wireless network device configured to transfer data wirelessly.

[0167] In one embodiment, at least one wireless network device is selected from a Wi-Fi adapter, a cellular modem, a Bluetooth module, a near-field communication chip (NFC), a wireless local area network (LAN) card, a wireless router, and a wireless access point. In one embodiment, the system is further configured to perform digital therapeutic interventions in any of the following forms: instructional videos, interactive videos including input and feedback from an individual, games, instructional prompts, question-and-answer surveys with feedback, virtual reality, augmented reality, or a combination thereof.

[0168] In one embodiment, the system further includes at least one additional device selected from a health monitoring system, medical device, haptic device, external speaker, headphones, virtual reality set, augmented reality glasses / device, biofeedback sensor, wearable activity tracker, smartphone, personal computing device, smart speaker, voice assistant, motion tracking sensor, virtual assistant system, internet hub, or a combination thereof, wherein at least one additional device is configured to transfer data between a person, a personal electronic device, or a combination thereof.

[0169] In one embodiment, the system is further configured to transfer data between the system and at least one additional device in order to personalize digital therapeutic interventions. In one embodiment, the health monitoring system is selected from wearable fitness trackers, remote patient monitoring (RPM) systems, telemedicine platforms, smart health devices, health and wellness apps, and hospital information systems (HIS).

[0170] In one embodiment, at least one digital intervention, a pharmaceutical agent, or a combination thereof is administered along with a conditioned stimulus selected from visual, auditory, tactile, or a combination thereof.

[0171] In one embodiment, the method further includes gamification elements.

[0172] In one embodiment, gamification elements are selected from badges, scores, leaderboards, rankings, game currency, quests or missions, characters or avatars, virtual goods, social media features, experience points (XP), or a combination thereof.

[0173] A patent or application file includes at least one drawing prepared in color. Copies of this patent or patent application publication containing color drawings are available by the Office upon request and payment of the necessary fees. To better understand the subject matter disclosed herein and to illustrate how it may be put into practice, embodiments are described herein, with reference to the attached drawings, only as non-limiting examples. [Brief explanation of the drawing]

[0174] [Figure 1A-1B] The image shows a screenshot of a digital maze. Figures 1A and 1B show different angles of the same maze from a first-person perspective. [Figure 2A-2D] Schematic representations of digital mazes of varying complexity are illustrated. Figure 2A shows six mazes with the same start-end location but different internal wall locations. Figure 2B shows another set of 12 mazes of varying complexity. Figure 2C shows a digital maze configuration in which the user must navigate along paths with varying widths (entrance and exit locations are marked with arrows). Figure 2D shows a digital maze configuration in which the user can take more than one path to reach the end location (entrance and exit locations are marked with arrows). [Figure 3] This is a schematic representation of the effects of digital therapy on neuroinflammation. [Figure 4A-4C]The longitudinal differences in seed-voxel connectivity are shown. Figure 4A shows the left hippocampal seed map. Figure 4B shows the right parahippocampal region seed map. (Post-intervention > pre-intervention resting-state brain imaging data - group level, n=17, PFDR<0.05, parametric statistics, bilateral). Figure 4C shows the correlation between changes in training scores and increased PHA3-dACC connectivity after training. PHA - parahippocampal region, dACC - dorsal anterior cingulate cortex. [Figure 5A-5B] The longitudinal difference seed-voxel connectivity map is shown. Figure 5A shows the posterior cingulate cortex (RSC) seed integrating both egocentric and allocentric spatial information streams. Post-training rsFC improvements were observed in both egocentric and allocentric networks (k=211, PFDR<0.002 and k=175, PFDR<0.004, respectively); (resting state brain imaging data post-intervention > pre-intervention, group level, n=17, PFDR<0.05, parametric statistics, two-sided). Figure 5B shows the Fisher Z effect size connectivity values, error bars, and CI bar graphs for the clusters. [Figure 6] The longitudinal difference seed-voxel connectivity map is shown. Increase in post-training rsFC between the spatial navigation network and left granular anterior insula cortex seeds (post-intervention > pre-intervention resting-state brain imaging data - group level, n=17, PFDR<0.05, parametric statistics, bilateral). [Figure 7] This report shows the change in CES-D scores. This intervention resulted in a significant decrease in self-reported CES-D depression scores. Following the intervention, CES-D (depression scale) scores decreased by 26.6% at the largest effect size (d=-0.829, p=0.004). Data are presented with mean ± SEM, p-values, and paired Student's t-test analysis. [Figures 8A-8C]Figure 8A shows DMN-SN ROI-to-ROI network connectivity. The default mode network (DMN) and salience network (SN) are inversely correlated in the brains of healthy, non-depressed individuals. Intra-network connectivity is shown in red, and inter-network connectivity is shown in blue. Figure 8B shows the decrease in intra-network connectivity within the DMN after intervention (z-score: 0.64±0.28 to 0.59±0.23, p<0.002). Figure 8C shows that improvement in CES-D depression scores (negative change indicates improvement in depressive state in post-hoc versus pre-hoc assessment) correlated with an increase in negative inter-network DMN-SN rsFC. This suggests a correlation between how much an individual subject improved in depression and how much healthier their connectivity pattern is (i.e., reflecting a greater inverse correlation between the DMN and SN (this inverse correlation is lost in depressed subjects)). [Figure 9A-9B] The results show increased post-training connectivity between the ventrolateral thalamus (VTL) and the premotor cortex, and a correlation between post-training VTL / premotor cortex connectivity and the time spent on training the subject. Figure 9C shows how digital therapy enhances the basal ganglia rsFC (seed: globus pallidus internal segment) and the rsFC in the frontal brain region, which are known to be impaired in Parkinson's disease. [Figure 9D-9F] This study demonstrates improved connectivity within the basal ganglia network and between somatosensory brain regions (seed: Putamne) (post-intervention > pre-intervention, resting state brain imaging data, group level, n=17, PFDR<0.05, parametric statistics, bilateral). [Figures 10A-10F] Psychological questionnaire results: Compared to the control group, the intervention group showed significant improvements in scores for depression (CES-D, p=0.22, see Figure 10A), stress / anxiety (STAI-S, p=0.028, see Figure 10B), resilience (BRCS, p=0.025, see Figure 10C), and emotional well-being (MHC-SF, p=0.043, see Figure 10D), as well as significant marginal improvements in additional measures of stress and anxiety (PSS, see Figure 10E; STAI-T, see Figure 10F). [Figures 11A-11F]The sustained effects of the intervention are highlighted by bar graphs recording the maintained or further improved questionnaire score improvements in the intervention group at the 3-week evaluation following the end of daily use of the mobile application. Charts are presented for depression scores (CES-D, Figure 11A), stress / anxiety (STAI-S, Figure 11B), resilience (BRCS, Figure 11C), and emotional well-being (MHC-SF, Figure 11D), and further improvements in additional measures of stress and anxiety (PSS, Figure 11E, and STAI-T, Figure 11F). [Figures 12A-12B] The effects of digital intervention on immune system biomarkers are shown. Figure 12A shows a graphical representation of the reduction in IL-17 in a blood sample due to the digital therapeutic intervention of the present invention. Figure 12B shows a graphical representation of the reduction in IL-18 in a saliva sample due to the digital therapeutic intervention of the present invention. [Figures 13A-13F] Significant changes in functional connectivity are observed in correlation with psychological improvement. Figures 13A and 13B show brain scans showing increased connectivity between the amygdala and the left and right mPFCs after intervention (resting-state brain imaging data post-intervention > pre-intervention - group level, n=27, PFDR<0.05, parametric statistics, two-sided). Figure 13C shows a bar graph of Fisher's Z effect size connectivity values, error bars, and CI for clusters. Figure 13D shows a graphical representation of a significant correlation between amygdala-mPFC rsFC and improvement in psychological scores for depression compared to control. Figure 13E shows a graphical representation of a significant correlation between amygdala-mPFC rsFC and improvement in psychological scores for well-being compared to control. Figure 13F shows a graphical representation of a significant correlation between amygdala-mPFC rsFC and improvement in psychological scores for stress compared to control. [Figure 14A-14D]This shows further outcomes for significant functional connectivity changes in correlation with psychological improvement. Figure 14A shows brain scans of reduced connectivity after intervention between the right amygdala and the left precuneus / superior parietal lobule. Figures 14B and 14C show cross-sections of the brain scans from Figure 14A (post-intervention > pre-intervention - group levels of resting-state brain imaging data, n=27, PFDR<0.05, parametric statistics, bilateral). Figure 14D shows a graphical representation of a significant correlation between amygdala-precuneus rsFC and improvement in psychological scores for stress compared to controls. [Figures 15A-15D] The correlation between changes in functional connectivity and a decrease in IL-18 levels due to digital therapeutic intervention is shown. Figures 15A and 15D show rsFC regression analysis demonstrating a significant correlation between the increase in hippocampal-dACC rsFCs and the improvement in IL-18 levels after intervention. Figures 15C and 15D show rsFC regression analysis demonstrating a significant correlation between the increase in parahippocampal-mPFC rsFCs and the improvement in IL-18 levels after intervention. [Figure 16A-16C] An example of a coordinated procedure protocol for perioperative ICB treatment in flowchart form is shown. The sequence of the procedure protocol is shown in Figure 16A, followed by Figure 16B. Figure 16C shows a separate procedure protocol, also called the patient journey from diagnosis and treatment decision to ongoing treatment. [Figures 17A-17E] The images show screenshots from a digital therapeutic intervention application on a mobile computing device. Figure 17A shows the start screen on a mobile phone app showing the necessary paths for navigating a digital maze. Figure 17B shows a first-person screenshot of a user navigating a digital maze. Figure 17C shows a screenshot of a partially obscured digital maze, one method to reduce reliance on visual cues for navigation within the maze. Figure 17D shows a screenshot of a heavily obscured digital maze. Figure 17E shows a screenshot of an instructional video on the mobile phone application platform. [Figure 18A-18I]The following are screenshots from a mobile phone app developed by Remepy. Figure 18A shows the home screen on the mobile phone app. Figure 18B shows the "welcome" screen. Figure 18C shows the "Explore tab" for browsing categories. Figure 18D shows tabs for accessing different digital interventions. Figure 18E shows the "range slider" function for wellness. Figure 18F shows the symptom prompt menu. Figure 18G shows the functions within the "safe place tab". Figure 18H shows the landing screen on the mobile phone app. Figure 18I shows the start screen before the user runs through the digital maze. [Figure 19] This paper illustrates various bodily networks affected by psychological interventions, along with a selection of correspondingly affected biomarkers.

[0175] For the sake of brevity and clarity of explanation, the elements shown in the diagrams are not necessarily drawn to scale, and the dimensions of some elements may be exaggerated relative to others. Furthermore, reference numbers may be repeated between drawings to indicate corresponding or similar elements. [Modes for carrying out the invention]

[0176] To gain a full understanding of the present invention, certain configurations and details are shown below. However, it will be apparent to those skilled in the art that the present invention can be carried out without the specific details presented herein. The various examples given throughout this description are merely descriptions of specific embodiments of the present invention, but the scope of the present invention is not limited to such examples. Any trademark names of drugs mentioned throughout this description are for demonstration purposes only.

[0177] As used in this description of the present invention, the terms “drug” or “pharmacotherapy” shall also include treatment with any medicinal product, whether or not it is approved by the relevant regulatory authority (e.g., the FDA).

[0178] For the ease of demonstrating the usefulness of the present invention, this description focuses primarily on neurodegenerative diseases such as Alzheimer's disease ("AD"), which is the most common type of dementia. However, the primary approaches and tools for treating AD described herein can also be implemented in mild cognitive impairment (MCI), which is an early stage of memory loss or other cognitive impairment in individuals who retain the ability to independently perform most activities of daily living, as well as in other types of dementia and neurodegenerative disorders involving cognitive decline.

[0179] Neurodegenerative disorders form a broad category of diseases characterized by the progressive degeneration and / or dysfunction of nerve cells (neurons) in the brain or peripheral nervous system. These disorders typically result in a progressive decline in cognitive function, motor control, or other neurological processes over time. Examples of neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). While the specific causes and mechanisms underlying each disorder vary, they often include the accumulation of abnormal protein aggregates, oxidative stress, inflammation, and genetic factors, or a combination of these factors.

[0180] Digital therapy to improve neural connectivity This invention provides methods for improving neural connectivity in an individual. In some embodiments, the terms “neural connectivity” and “neuroplasticity” are used interchangeably because their effects are correlated. “Neuroplasticity” generally refers to the brain’s ability to reorganize itself by forming new neural connections in response to interventions, learning, experience, and environmental changes, etc. “Neuroconnectivity” generally refers to the interconnectivity and communication pathways between different regions of the nervous system, particularly the brain. As will become clear, the interventions are aimed at improving neural connectivity, neuroplasticity, or a combination thereof. As used herein, “neural connectivity” is also referred to as “synaptic connectivity,” “brain connectivity,” etc. As used herein, the terms “increase,” “improve,” and “modulate” are used interchangeably when the effects are the same. For example, if increasing neural connectivity also improves neural connectivity, the terms are considered interchangeable. However, among the various markers disclosed herein, an “increase” of a particular marker may refer to a “decrease” of a particular effect.

[0181] In one embodiment, the present invention provides a method for increasing neural connectivity in an individual, and this method is This includes individuals performing at least one digital intervention from among sensory inhibition, sensory substitution, sensory integration, or a combination thereof.

[0182] In one embodiment, the present invention provides a method for increasing neural connectivity in an individual, and this method is This includes individuals implementing a digital therapeutic intervention plan that includes at least one digital intervention, which may involve sensory suppression, sensory substitution, sensory integration, or a combination thereof.

[0183] In one embodiment, at least one digital intervention is included within the digital therapeutic intervention plan.

[0184] In one embodiment, the present invention provides a method for increasing neural connectivity in an individual, the method comprising performing at least one digital intervention including sensory inhibition. In one embodiment, the present invention provides a method for increasing neural connectivity in an individual, the method comprising performing at least one digital intervention including sensory substitution. In one embodiment, the present invention provides a method for increasing neural connectivity in an individual, the method comprising performing at least one digital intervention including sensory integration. As understood herein, sensory inhibition, substitution, and integration can be used individually or in any combination to perform digital interventions. Individualization of an individual's digital therapeutic intervention plan is tailored to each individual, but general guiding principles can be used to design the intervention plan. As described below, digital intervention plans can be commonly available through multiple digital interventions using the three principles of sensory inhibition, substitution, and integration, some based on cognitive interventions, psychological interventions, physical interventions, or a combination thereof.

[0185] As used herein, those who use or receive digital therapeutic interventions are referred to in multiple ways. For example, “user” may also be referred to as “patient,” “individual,” “subject,” “participant,” or “recipient,” and these terms may be understood interchangeably.

[0186] In one embodiment, a method for increasing neural connectivity in an individual includes at least one cognitive intervention. In one embodiment, a method for increasing neural connectivity in an individual includes at least one psychological intervention. In one embodiment, a method for increasing neural connectivity in an individual includes at least one physical intervention. In one embodiment, a digital intervention includes at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof. In one embodiment, a digital intervention includes at least one cognitive intervention and at least one psychological intervention. In one embodiment, a digital intervention includes at least one cognitive intervention and at least one physical intervention. In one embodiment, a digital intervention includes at least one psychological intervention and at least one physical intervention.

[0187] As used herein, “digital intervention” refers to the use of a digital platform, at least partially, to perform a therapeutic intervention. “Digital intervention” is understood similarly regardless of which digital intervention or combination intervention is described. For example, the term can be used to describe methods for increasing neural connectivity, methods for improving immune function, etc. In various embodiments, digital intervention refers to the use of digital technologies, such as mobile applications, web-based platforms, virtual reality, or wearable devices, to provide therapeutic interventions aimed at improving mental health, physical well-being, management of a medical condition, or a combination thereof. These interventions may include, as described, cognitive behavioral therapy, mindfulness exercises, guided meditation, remote monitoring of health parameters, personalized health coaching, and other forms of support or treatment delivered through digital channels. In various embodiments, the terms “digital treatment” and “digital intervention” are understood interchangeably in that both refer to the use of digital technologies to provide therapeutic interventions aimed at improving mental health, physical well-being, or management of a medical condition. Accordingly, the phrases “digital treatment plan,” “digital treatment intervention plan,” “digital treatment course,” and “digital treatment schedule” are to be understood interchangeably in light of the definitions disclosed herein. In one embodiment, “digital treatment intervention plan” refers to multiple digital treatment interventions. In one embodiment, the digital treatment intervention plan includes at least one digital intervention. In one embodiment, the digital treatment intervention plan includes multiple digital interventions. In some embodiments, the digital treatment intervention plan includes not only digital interventions but also non-digital treatment interventions.

[0188] Digital therapeutic interventions are also referred to as “sessions” in this specification. In one embodiment, the number of sessions varies within the range of 1 to 10 digital therapeutic interventions. In one embodiment, the number of sessions varies within the range of 1 to 100 digital therapeutic interventions. In one embodiment, the number of sessions varies within the range of 1 to 1000 digital therapeutic interventions. In one embodiment, the number of sessions varies within the range of 1 to 10000 digital therapeutic interventions. In one embodiment, the number of sessions varies within the range of 1 to 100000 digital therapeutic interventions. In one embodiment, the number of sessions varies within the range of 1 to 1000000 digital therapeutic interventions.

[0189] In one embodiment, a digital intervention includes at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof. As used herein, “cognitive” interventions are generally directed towards interventions that utilize tasks affecting cognition, brain function, etc., as described. Thus, cognitive interventions generally relate to reasoning tasks, memory improvement interventions, sensory interventions, etc. In various embodiments, cognitive interventions may be understood as “neurocognitive.” The main idea is that some interventions are inherently psychological and are often directed towards reducing stress and other kinds of discomfort, while others are directed towards increasing connectivity. Note that any new learning brings about new neural connectivity.

[0190] As used herein, “psychological” interventions generally refer to interventions that affect an individual’s psychological and / or behavioral aspects. Therefore, psychological interventions generally relate to behavioral, social, and psychological tasks, as described herein. “Physical” interventions generally refer to interventions that improve an individual’s motor function, as used herein.

[0191] All psychological, cognitive, physical, or combination thereof, on a digital platform utilize one of the following: sensory inhibition, sensory substitution, sensory integration, or a combination thereof. This is also referred to as the “sensory principle,” i.e., an intervention that relies on sensory inhibition, sensory substitution, sensory integration, or a combination thereof. Thus, “sensory principles” used for different purposes in various embodiments of the present invention are used in equivalent ways in one embodiment. For example, a psychological intervention that utilizes the sensory principle may also be used for cognitive and / or physical interventions. However, the specific implementation of the sensory principle for each or more interventions varies from person to person and / or from disease / disability to disease / disability.

[0192] In various embodiments, digital interventions are performed on personal electronic devices. As will become apparent, digital interventions may be performed on at least one personal electronic device, depending on the type of intervention and / or the intervention plan. These personal electronic devices may be used in any digital therapeutic intervention plan disclosed herein and may also be used for any described purposes, such as increasing neural connectivity, improving immune function, or improving motor skills. As used herein, the term “personal electronic device” is understood to mean any electronic device used by a user to perform any part of a digital intervention. Thus, it is understood to include devices that are often “personal” devices but are not directly owned by the user, but are used / synchronized with the user to implement the digital intervention. The following are examples of personal electronic devices, but are not limited to: smartphones, tablets, wearable devices, smart TVs, computers, laptops, e-readers, game consoles, smartwatches, fitness trackers, portable media players, digital cameras, virtual reality (VR) headsets, augmented reality (AR) devices, portable GPS devices, portable Bluetooth devices, portable digital assistants, smart glasses and audio devices, or any combination thereof. In various embodiments, the personal electronic device is a mobile computing device.

[0193] The data utilized by the methods described herein include all diverse data types necessary for implementing digital therapeutic interventions. Thus, these data, corresponding analyses, and adaptive plans are used for any digital therapeutic intervention plans disclosed herein, for any described purposes such as increasing neural connectivity, improving immune function, or improving motor skills. In various embodiments, the methods described herein are understood to be performed on corresponding systems, devices, networks, etc., to perform the data transfer and data analysis required to carry out the methods of the invention. As understood herein, the term “data transfer” includes any of the following selected means: sending, receiving, sharing, synchronizing, backing up, restoring, and importing / exporting data. In this manner, the method further includes transferring data for an individual, where the data is selected from personal information, demographic information, medical information, biomarker information, drug intake and medication regimens, geographic information, environmental information, lifestyle information, health and well-being, biometric information, behavioral information, digital intervention-related data, goal setting, medical considerations, health and well-being, preferences, availability, time constraints, scheduling, individual strengths and weaknesses, cultural considerations, communication channel preferences, feedback from the individual, feedback from healthcare providers, or a combination thereof.

[0194] In various embodiments, data entry for digital therapy may take any form. Examples of data, but are not limited to, include name, age, sex, gender, marital status, ethnicity, race, children, socioeconomic status, occupation, geographical location, location of pain, frequency of pain, intensity of pain, type of pain, disability status, anxiety assessment, type of medical intervention, medication dosage, date, time, sleep cycle, calendar entries, side effects, allergies, concomitant medications, symptoms or changes thereof, diet, lifestyle factors, test results, medical intervention schedule, weight, height, mental health, general health, medication list, diet, exercise regimen, existing medical status, genetic information, lifestyle factors, daily activities, protocol adherence, medical appointment schedule, or any combination thereof. Each of these data categories may relate to the others. For example, an anxiety score (or "rank") may be associated with any of the following, but not limited to: increased heart rate, chest tightness, shortness of breath, feeling of choking, tremors, sweating, dizziness, nausea, reflux, numbness, stomach ache, body aches, loss of appetite, elevated body temperature, or any combination thereof.

[0195] Data may be received before, during, and / or after any intervention described herein. The data may be incorporated into the corresponding digital treatment program or entered by the individual, an administrator, or otherwise.

[0196] Thus, the Method of the Invention further includes analyzing data in any form to adapt a digital intervention (and / or corresponding plan) to the individual. In one embodiment, the Method includes analyzing data by machine learning, artificial intelligence (AI), statistical modeling, or a combination thereof, thereby adapting at least one digital intervention to the individual at the start of the Method and generating a digital therapeutic intervention plan. In one embodiment, the Method includes analyzing data by machine learning, artificial intelligence (AI), statistical modeling, or a combination thereof to adapt the digital therapeutic intervention plan. As understood herein, “digital therapeutic intervention plan” refers to a plan comprising at least one digital intervention for an individual. Terms such as “digital therapeutic intervention plan,” “intervention plan,” and “digital therapeutic plan” are used interchangeably. For example, a digital therapeutic intervention plan may comprise multiple digital interventions. A digital intervention is also referred to herein as a “session.” A digital therapeutic plan is a structured program comprising a set of digital interventions / sessions designed to address an individual’s specific mental health or well-being needs. As shown, digital therapeutic intervention plans take into account various factors, including initial assessment, goal setting, intervention selection, timing, dosage and frequency, regimen, schedule, progress tracking, adjustment and adaptation, support resources, and integration with other procedures. For example, an initial intervention plan for a particular disease may be general and will adapt as the individual progresses through the intervention plan. Different individuals will perform and respond differently to an initial standardized plan. Thus, in one embodiment, the digital intervention plan is standardized externally. In other embodiments, the captured data is used to personalize the digital intervention plan at the start of the method. Furthermore, as described, the digital intervention itself, as well as the digital intervention plan, can all be individualized according to the individual's needs and goals.

[0197] In one embodiment, the degree of improvement achieved by the individual implementing the digital therapeutic intervention plan is determined by analysis. In one embodiment, the analysis is for adapting the digital intervention. In one embodiment, the method further includes providing instructions to the individual before, during, and / or after any stage of the digital therapeutic intervention plan. The analysis function is applied to any digital therapeutic intervention plan for any of the described objectives, such as increased neural connectivity, improved immune function, or improved motor skills.

[0198] In one embodiment, the digital intervention includes at least one psychological intervention. As understood herein, a variety of psychological interventions can be used for the digital intervention, and the list shown is just one example of many of them, but different combinations are used according to the purpose and intent of the intervention. Therefore, while a list of interventions is provided, it is understood that some of those specific interventions may be excluded if they are not relevant to the digital intervention of a particular individual. Examples of psychological interventions, but not limited to these, include, but are: guided imaging, psychoeducation, psychotherapy, cognitive behavioral therapy, stress and anxiety management training, mindfulness-based interventions, body scanning training, sleep hygiene, fatigue training, acceptance and commitment therapy (ACT), dialectical behavior therapy (DBT), psychodynamic therapy, solution-focused brief therapy (SFBT), narrative therapy, pain therapy, addiction therapy, gestalt therapy, behavioral activation therapy, telepsychiatry and teletherapy, or combinations thereof. In one embodiment, the psychological intervention is attention training.

[0199] Figure 19 shows various bodily networks affected by psychological interventions, along with a selection of correspondingly affected biomarkers. This figure illustrates the interconnectivity of these biomarkers and whether they increase or decrease in response to psychological interventions.

[0200] In various embodiments, "psychoeducation" is an intervention that provides individuals with information and tools to better understand and manage their mental health status or concerns. "Body scanning training" typically refers to a mindfulness practice in which an individual systematically directs attention to different parts of their body, often starting from the toes and moving upwards to the head. This practice aims to enhance bodily awareness, promote relaxation, and cultivate a deeper mind-body connection. It is commonly used as a technique in mindfulness-based stress reduction (MBSR) programs and other mindfulness-based interventions.

[0201] In one embodiment, the digital intervention includes at least one cognitive intervention. As understood herein, a variety of cognitive interventions can be used for the digital intervention, and the list shown is just one example of many of them, but different combinations are used according to the purpose and intent of the intervention. Therefore, while a list of interventions is provided, it is understood that some of those particular interventions may be excluded if they are not relevant to the digital intervention of a particular individual. Examples of cognitive interventions, but not limited to these, include, maze navigation, spatial navigation, Magic 7 training, memory enhancement techniques, attention training, problem solving, sonification exercises, data visualization, geometric puzzles, shape and pattern matching, visual cognitive tasks, spatial reasoning games, face detection training, drawing games, concentration training, reading comprehension training, or any combination thereof.

[0202] Magic-7 training refers to a cognitive exercise or game designed to challenge and improve memory recall skills. In this game, participants are presented with a list of seven random items or pieces of information to memorize. After a short period of time to learn the list, the items are hidden or removed, and participants are asked to recall as many items as possible from the list. As understood herein, the sensory principle can be applied to Magic-7 memory training, for example, a user is asked to recall seven items on a screen, and then some of the items are replaced with auditory cues that the user needs to remember.

[0203] In one embodiment, the digital intervention includes at least one physical intervention. As understood herein, a variety of physical interventions can be used for the digital intervention, and the list shown is just one example of many of them, but different combinations are used according to the purpose and intent of the intervention. Examples of physical interventions, but not limited to these, include, physiotherapy, voice therapy, speech therapy, swallowing therapy, breathing training, saliva and drooling therapy, chewing therapy, facial expression training, tremor management, mobility training, freeze and stiffness exercises, tapping training, limb agility exercises, volume-sustain-pitch training, training for gait freeze, motor function therapy, dance therapy, handwriting training, balance exercises, postural stability training, strength training, stretching exercises, coordination training, metronome training, fine motor skills training, or combinations thereof.

[0204] Metronome training refers to a therapeutic technique that uses rhythmic auditory stimuli to improve various cognitive or motor functions, such as motor coordination, attention / concentration, timing / rhythm perception, and anxiety / stress.

[0205] The maze interventions described herein are digital mazes. This includes digital mazes on a 2D screen, or virtual reality and / or augmented reality experiences. Examples of mazes, but not limited to, include the Hebb-Williams maze, Morris water maze, Barnes maze, radial arm maze, T-maze, and elevated plus maze. As used herein, “digital maze” refers to any maze that is implemented in at least partially digital form. Thus, the presented examples of mazes, such as the Hebb-Williams maze, are understood as at least partially digital implementations of these mazes. For example, a maze may be navigated on a software application on a personal electronic device. Since embodiments demonstrate that mazes utilizing augmented reality and virtual reality are implemented at least partially in digital space as well as physical space, it should be noted that these digital mazes may be implemented “at least partially” in digital space.

[0206] As described herein, and in various embodiments, digital interventions include sensory inhibition, sensory substitution, sensory integration, or a combination thereof. Any individual intervention described herein may include sensory inhibition, sensory substitution, sensory integration, or a combination thereof. Thus, when referring to a particular digital intervention, it is understood that the sensory principles apply. The “sensation” referred to herein is any of the following: vision, hearing, touch, smell, and taste. In various embodiments, sensation refers to vision, hearing, and touch. Examples of sensory modalities and their corresponding inputs include vision, hearing, touch, taste, smell, proprioception, and vestibular sensation, all of which can be understood as being included in the sensory principles outlined herein. The “sensation” may also be referred to as “human sensory modal,” “sensory modal,” or “modal,” and these terms may be used interchangeably and understood. The “inputs” and “cues” corresponding to these sensory modalities may be understood interchangeably. Furthermore, when referring to different modalities, different expressions may be used to describe them. For example, an image may be described as a visual cue / stimulus / image, and an auditory cue may be referred to as “sound.” Experts understand that the use of these terms is interchangeable depending on the context in which they are referred. In one embodiment, “sensory suppression” refers to at least partial suppression of at least one human sensory modal input. Suppression refers to an implementation in which one modality is reduced or at least partially eliminated, for example, covering one eye suppresses the individual’s visual ability, or lowering the volume of a melody reduces / suppresses the auditory input to that individual. In one embodiment, the at least one human sensory modal input is selected from visual, auditory, and tactile. As understood herein, “sensory substitution” refers to at least partially substituting at least one human sensory modal input with at least one other human sensory modal input. For example, an individual may be presented with a visual video clip without sound, and then the visual cue becomes more blurred, and the auditory cue substitutes the visual cue in a corresponding manner. One example is sound directly related to an image, such as the visual appearance of waves breaking on a shore and the sound of waves breaking on a shore. In various embodiments, individual training with sensory substations results in improved neural connectivity.In one embodiment, at least partial substitution of at least one sensory modality input with at least one other sensory modality input is performed. From sight to hearing and / or touch, From hearing to sight and / or touch, The sense of touch is selected from sight and / or hearing.

[0207] The integration of multiple sensory modal inputs is achieved by combining sensory modal inputs. As understood herein, and in one embodiment, “integration” with respect to sensory modals refers to the integration of modal inputs, for example, using visual cues and auditory cues together. In one embodiment, sensory integration refers to at least a partial combination of at least two sensory modal inputs. In one embodiment, a personal electronic device, at least one additional device, or a combination thereof, is configured to provide sensory modal inputs for performing sensory inhibition, sensory substitution, sensory integration, or a combination thereof. In various embodiments, the integration of sensory modal inputs includes the following modalities: visual, auditory, and tactile. For example, visual and auditory cues may be experienced together, for example, if a particular sound (auditory) corresponds to a particular image (visual). These may further be integrated with a vibration (tactile) sensation coupled with auditory and visual cues so that the same event at time is experienced by an individual, but in different modalities.

[0208] In one embodiment, a digital intervention includes an individual interacting with a personal electronic device using any of the following means selected from touch gestures, motion gestures, voice commands, text input, camera and media interaction, sensor-based interaction, or a combination thereof. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, includes an individual interacting with a personal electronic device using any of the following means selected from touch gestures, motion gestures, voice commands, text input, camera and media interaction, sensor-based interaction, or a combination thereof. Examples of touch gestures include, but are not limited to, tapping, swiping, scrolling, pinching, dragging, double-tapping, or a combination thereof. Examples of motion gestures include, but are not limited to, tilting, shaking, rotating, body movements, weaving, or a combination thereof. Examples of camera and / or media interactions include, but are not limited to, taking photos, recording videos, uploading / downloading images, uploading / downloading audio, uploading / downloading videos, augmented reality, or a combination thereof.

[0209] In various embodiments, sensor-based interactions are performed by a global positioning system (GPS) system, accelerometer, gyroscope, proximity sensor, or a combination thereof, selected from the above.

[0210] Various digital formats may be used to carry out the digital intervention of the present invention. In one embodiment, at least one digital intervention is carried out in the form of an instructional video, an interactive video including input and feedback from an individual, a game, an instructional prompt, a question-and-answer survey with feedback, virtual reality, augmented reality, or a combination thereof.

[0211] The duration for which each intervention is performed depends on the individual's specific applications, schedule, regimen, etc. The following embodiments regarding the duration of the digital interventions referred to herein apply to all digital interventions referred to herein and to any purpose referred to herein. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, spans a period ranging from 1 second to 60 minutes. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, spans a period ranging from 1 second to 30 minutes. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, spans a period ranging from 1 second to 10 minutes. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, spans a period ranging from 1 second to 5 minutes. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, spans a period ranging from 1 second to 1 minute. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, lasts for a period of 1 to 5 minutes. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, lasts for a period of 5 to 10 minutes. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, lasts for a period of 10 to 30 minutes. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, lasts for a period of 30 to 60 minutes.

[0212] Embodiments defining the duration of a digital therapeutic intervention plan are applicable to all digital therapeutic intervention plans disclosed herein for any purpose described, such as improving neural connectivity or improving immune function. In some embodiments, the digital therapeutic intervention plan is implemented over a period of 1 day to 10 years. In some embodiments, the digital therapeutic intervention plan is implemented over a period of 1 day to 5 years. In some embodiments, the digital therapeutic intervention plan is implemented over a period of 1 day to 1 year. In some embodiments, the digital therapeutic intervention plan is implemented over a period of 1 day to 6 months. In some embodiments, the digital therapeutic intervention plan is implemented over a period of 1 day to 3 months. In some embodiments, the digital therapeutic intervention plan is implemented over a period of 1 day to 2 months. In some embodiments, the digital therapeutic intervention plan is implemented over a period of 1 day to 1 month. In some embodiments, the digital therapeutic intervention plan is implemented over a period of 1 day to 3 weeks. In some embodiments, the digital therapeutic intervention plan is implemented over a period of 1 day to 1 week.

[0213] Digital intervention plans require individualization to be tailored to the individual implementing the plan. Therefore, the methods of the present invention include adaptation plans incorporated into the digital intervention plan. Adaptation plans apply to all digital intervention plans disclosed herein and to any of the described objectives, such as improving neuroconnectivity or improving immunity. In one embodiment, the methods of the present invention, in the course of a digital therapeutic intervention plan, Receiving data and, Receiving updated data in accordance with at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, Analyzing data and updated data using machine learning, artificial intelligence (AI), or statistical modeling, This further includes adaptive plans, which include generating updated digital therapeutic intervention plans for individuals based on the analysis of updated data.

[0214] Therefore, all data collected at any point in the digital intervention plan process will be stored and analyzed to provide personalization to individuals.

[0215] In one embodiment, the adaptation includes changes in any of the following, selected from: the type of intervention, the order of interventions, the frequency of interventions, the intensity of interventions, the length of interventions, the difficulty of interventions, the sensory modal inputs used, the level of interaction, or a combination thereof. For example, if an individual completes a task relatively quickly, a particular intervention may be adapted to be more intense, longer, or more difficult. Or, if an individual provides feedback that they are overwhelmed by the amount of time spent performing digital intervention sessions or the digital intervention plan itself, the intervention plan may be adapted to include fewer sessions over a period of time. Another example is if an individual finds a particular session boring and / or uninteresting (even if this is still an important element in the individual's intervention plan), it may be scheduled at a different time of day, or that particular intervention may be performed less frequently or for less duration. For example, the adaptation may include changes to any of the sensory modal inputs used, individually or in combination.

[0216] Similar to the digital intervention plan itself, multiple external devices may be used in conjunction with the method of the present invention to further advance the goal of providing a digital therapeutic intervention (and associated plan) to an individual. Additional devices used for the digital therapeutic intervention plan may be applied to any of the digital therapeutic intervention plans for any of the described objectives, such as increased neural connectivity, improved immunity, or improved motor skills. In one embodiment, the method further includes at least one additional device selected from a health monitoring system, medical device, haptic device, external speaker, headphones, virtual reality set, augmented reality glasses / device, biofeedback sensor, wearable activity tracker, smartphone, personal computing device, smart speaker, voice assistant, motion tracking sensor, virtual assistant system, internet hub, or a combination thereof. In one embodiment, at least one additional device is configured to transfer data between an individual, a personal electronic device, or a combination thereof. Examples of health monitoring systems, but not limited to, include wearable fitness trackers, remote patient monitoring (RPM) systems, telemedicine platforms, smart health devices, health and wellness apps, and hospital information systems (HIS).

[0217] These additional devices are configured to provide at least one of the following: real-time feedback to individuals based on collected data and interactions, measurement of health parameters, outputting signals to individuals, real-time customization of digital therapeutic intervention plans, monitoring of individual engagement with and adherence to treatment protocols, remote monitoring, inter-device cloud synchronization and data sharing, or a combination thereof. Providing real-time feedback may include interactions with any digital platform and digital therapeutic intervention sessions, such as questionnaires taken in the course of a series of interventions.

[0218] In one embodiment, a personal electronic device, at least one additional device, or a combination thereof is configured to provide a sensory modal input.

[0219] The digital interventions of the present invention provide methods for treating, preventing, or alleviating symptoms in individuals suffering from various diseases, but these methods can also be used by individuals who are not otherwise suffering from these diseases, for example, those aiming to increase general well-being by improving neurological function. Furthermore, any digital therapeutic intervention and its corresponding objective (e.g., increased neuroconnectivity, improved immune function) may be understood as being used to treat, prevent, alleviate, or combine symptoms. Thus, "treating, preventing, or alleviating symptoms" may be understood in various embodiments as each of these being done individually or in combination. Since the methods of the present invention are effective in any of these areas, their ability to treat / prevent / alleviate symptoms is often considered together.

[0220] In one embodiment, the present invention provides a method for increasing neural connectivity to treat, prevent, or alleviate symptoms in individuals suffering from neurodegenerative diseases. Examples of neurodegenerative diseases, but not limited to, include Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, chronic traumatic encephalopathy (CTE), Lewy body dementia (LBD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), Huntington's disease, Creutzfeldt-Jakob disease, and Wilson's disease.

[0221] In one embodiment, the present invention provides a method for increasing neuroconnectivity to treat, prevent, or alleviate symptoms in individuals suffering from neurological disorders. Examples of neurological disorders, but not limited to, include mild cognitive impairment (MCI), sleep disorders, migraines and headache disorders, neuropathy, epilepsy, traumatic brain injury, spinal cord injury, and cerebrovascular disease.

[0222] In one embodiment, methods for increasing neuroconnectivity are used to treat, prevent, or alleviate symptoms in individuals suffering from psychological disorders. Examples of psychological disorders, but not limited to, include depression, anxiety, bipolar disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), attention-deficit / hyperactivity disorder (ADHD), eating disorders, substance use disorders, sleep disorders, autism spectrum disorder (ASD), personality disorders, schizophrenia, and dissociative disorders.

[0223] Combination digital therapy to improve neural connectivity The present invention provides combination therapies for improving neuroconnectivity, therapies comprising administering at least one digital therapy and performing at least one non-digital medical intervention. In one embodiment, the combination therapy for improving neuroconnectivity comprises administering at least one digital therapy and administering at least one pharmaceutical agent. The term “combination” (or “combination method”) is used to describe any intervention comprising at least one digital therapy intervention and at least one non-digital therapy intervention. Thus, in any method disclosed herein, a “single” method utilizing only a digital therapy intervention is used so as to be equally included within a “combination” intervention. Therefore, all methods directed toward improving neuroconnectivity that utilize only a digital intervention can be understood as being used in combination with the various non-digital interventions disclosed. The same applies to other methods that affect other biological processes, such as improving immune function and improving motor function. One of the advantages of the present invention lies in its combination with known drug therapies, thereby helping to improve outcomes.

[0224] In various embodiments and as used herein, the terms “drug,” “pharmaceutical,” “medicinal agent,” “pharmaceutical,” and “medicine” are understood to be interchangeable. That is, they refer to any substance used to diagnose, prevent, treat, or alleviate symptoms of a medical condition. They may also refer to substances that, in general, are intended to maintain or improve an individual’s well-being without targeting a specific disease. Accordingly, in various embodiments, “medicinal agent” may refer to a dietary supplement, as will be described in detail. As used herein and as used herein, “treatment” of any disease includes any intervention that alleviates symptoms or improves at least one marker of that disease. Accordingly, “treatment” may also refer to delaying or preventing the onset of a disease, as understood herein.

[0225] In one embodiment, the present invention provides a method for increasing neural connectivity in an individual, and this method is Individuals performing at least one digital intervention from sensory inhibition, sensory substitution, sensory integration, or a combination thereof, This includes administering at least one non-digital medical intervention before, during, or after at least one digital intervention, or a combination thereof.

[0226] In some embodiments, non-digital medical interventions are selected from pharmaceuticals, medical procedures, physiotherapy, psychotherapy, psychiatry, rehabilitation, lifestyle interventions, nutritional supplements, mineral supplements, and physical exercise.

[0227] To understand combination therapy, in one embodiment, the administration of a non-digital intervention takes place before at least one digital therapeutic intervention. In another embodiment, the administration of a non-digital medical intervention takes place during at least one digital intervention. In yet another embodiment, the administration of a non-digital medical intervention takes place after at least one digital intervention. Since it is stated that a digital intervention plan includes multiple sessions and / or digital interventions, the administration of a non-digital medical intervention as part of the plan does not necessarily have to be linked to the same digital intervention for each combination therapy intervention. For example, in one digital therapeutic intervention plan, a particular drug is administered to an individual once a month, but the digital intervention is not necessarily the same from month to month. For example, during the first administration, the individual may receive a 5-minute psychological-based therapy, while during the second administration, the individual may receive a cognitive-based therapy. The type of digital intervention can vary each time the drug is administered, so as to be linked to the drug administration. This also applies to the specific dosage of the drug, the intensity / frequency / type of the digital intervention, etc. Also, as disclosed, combination therapy can be used as a means of conditioning an individual to improve the function of the drug itself. Conditioning individuals in this manner can be achieved through positive reinforcement via digital cues and interventions as described herein. For example, concurrent administration of medicinal agents in parallel with digital therapy can modulate the immune response, improve motor function, improve neuroconnectivity / plasticity, improve treatment outcomes, or reduce treatment-related toxicity. Administration of medicinal agents between digital therapies can also take the form of continuous infusions or periodic dosing of medicinal agents during the course of treatment to maintain optimal function or to target specific markers in real time, i.e., in response to performing the digital therapy. Medicinal agent administration may also be performed after digital therapy. Post-treatment administration of medicinal agents can help support immune recovery, reduce the risk of infection, or prevent disease recurrence after completion of digital therapy. Administration of medicinal agents as part of a maintenance regimen to maintain immune / neurological function or to extend treatment benefits after completion of digital therapy.

[0228] Another example of combining digital therapy with medical interventions is to synchronize administration with specific points in the patient journey, for example, at the peak of a particular marker. Medicinal drug administration may be performed at the peak expression or activity of a particular marker (e.g., immune / neuroactive) to capitalize on its heightened responsiveness or to most effectively target a pathological process. Alternatively, the administration of a medicinal drug may be timed to coincide with a peak inflammatory response or immune activation associated with a particular marker to maximize therapeutic efficacy. Therefore, the timing of any digital intervention, non-digital medical intervention, or combination thereof is considered to be within the scope of this invention.

[0229] The application of digital interventions and / or the administration of pharmaceutical agents may be carried out at various points in an individual's treatment plan. For some pharmaceutical agents, they are administered before treatment and / or procedures. One such example is administering a pharmaceutical agent before the initiation of a particular treatment to reset the immune system or to enhance the effectiveness of subsequent treatments. Another example is pretreatment with pharmaceutical agents to mitigate potential side effects or adverse reactions associated with treatment.

[0230] Numerous pharmaceutical agents are available to improve human neuroconnectivity. Examples of such agents include, but are not limited to, dopaminergic agonists, anti-amyloid-beta antibodies, opioids, immune checkpoint inhibitors, NMDA receptor antagonists, triptans, acetylcholinesterase inhibitors, neurosteroids, anti-inflammatory agents, neuroprotective agents, mitochondrial support agents, metabolic therapies, hormone therapies, tau-targeted therapies, beta-secretase inhibitors, gamma-secretase modulators, or combinations thereof.

[0231] In one embodiment, the dopaminergic agonist is selected from dopamine precursors, dopamine agonists, monoamine oxidase inhibitors (MAOIs), or a combination thereof. In one embodiment, the dopamine precursor is selected from levodopa, levodopa, levodopa-carbidopa, levodopa-benserazide, levodopa-carbidopa-entacapone, and foslevodopa-foscarbidopa. In one embodiment, the dopamine agonist is selected from pramipexole, ropinirole, rotigotine, apomorphine, bromocriptine, cabergoline, pergolide, and lislide. In one embodiment, the monoamine oxidase inhibitor is selected from selegiline, rasagiline, and safinamide. In one embodiment, the anti-amyloid-beta antibody is selected from lecabemab, aducanumab, solanezumab, gantenerumab, crenezumab, donanemab, or a combination thereof. In one embodiment, the opioid is selected from morphine, fentanyl, oxycodone, hydrocodone, buprenorphine, codeine, hydromorphone, meperidine, tapentadol, butorphanol, pethidine, levorphanol, methadone, dextropropoxifen, tramadol, ketobemidone, or a combination thereof. In one embodiment, the NMDA receptor antagonist is selected from SAGE-718, membrolizumab, nivolumab, cemiprimab, PD-L1 inhibitors, avelumab, atezolizumab, durvalumab, CTLA-4 inhibitors, ipilimumab, tremelimumab, LAG-3 inhibitors, relatrimab, TIM-3 inhibitors, sabatrimab, TIGIT inhibitors, tiragolumab, domvanarimab, CD40 agonists, sericrelumab, OX40 agonists, utomirumab, GITR agonists, tiragolumab, IDO1 inhibitors, VISTA inhibitors, B7-H3 inhibitors, or combinations thereof. In one embodiment, the NMDA receptor antagonist is selected from SAGE-718, memantine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N2O), ketamine, or combinations thereof. In one embodiment, the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine, galantamine, or a combination thereof.In one embodiment, the neurosteroid is selected from allopregnanolone, dehydroepiandrosterone, pregnenolone, progesterone, androstenediol, estradiol, testosterone, or a combination thereof. In one embodiment, the anti-inflammatory agent is selected from nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, biological agents, or a combination thereof. In one embodiment, the anti-inflammatory agent is selected from ibuprofen, naproxen, aspirin, celecoxib, diclofenac, prednisone, hydrocortisone, dexamethasone, prednisolone, methylprednisolone, tumor necrosis factor (TNF) inhibitors, interleukin (IL) inhibitors, Janus kinase (JAK) inhibitors, interleukin-1 (IL-1) receptor antagonists, interleukin-6 (IL-6) inhibitors, interleukin-17 (IL-17) inhibitors, disease-modifying antirheumatic drugs (DMARDs), colchicine, or a combination thereof. In one embodiment, the neuroprotective agent is selected from allopregnanolone, dehydroepiandrosterone, pregnenolone, progesterone, androstenediol, estradiol, testosterone, ketamine, riluzole, antioxidants, vitamin E, vitamin C, alpha-lipoic acid, omega-3 fatty acids, coenzyme Q10 (CoQ10), ginkgo biloba extract, melatonin, resveratrol, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glutathione, magnesium, L-carnitine, carnosine, N-acetylcysteine ​​(NAC), curcumin, quercetin, green tea extract, bacopa monnieri, ginseng, huperzine A, or a combination thereof. In one embodiment, the nutritional supplement is selected from vitamin B, vitamin B12, omega-3 fatty acids, magnesium, zinc, iron, folic acid, vitamin C, vitamin E, probiotics, ginkgo biloba, curcumin, coenzyme Q10, acetyl-L-carnitine, alpha-lipoic acid, phosphatidylserine, bacopa monnieri, ashwagandha, rhodiola rosea, L-theanine, melatonin, or a combination thereof.

[0232] In one embodiment, the pharmaceutical agent is administered by injection, oral, topical, inhalation, transdermal, nasal, intravenous, intramuscular, subcutaneous, or a combination thereof.

[0233] In one embodiment, the combination method for improving neural connectivity is further configured to achieve increased neural connectivity, thereby configuring the digital therapeutic intervention plan to take into account the individual's drug intake, medication regimen, and non-digital medical intervention schedule. In one embodiment, the drug is administered with a conditioned stimulus selected from visual, auditory, tactile, or a combination thereof.

[0234] Digital therapies to improve immune function Note that the terminology used in digital therapeutic methods is consistent and applicable to both digital therapeutics and related interventions. In one embodiment, the method is intended to treat, prevent, or alleviate symptoms in individuals with Parkinson's disease, Alzheimer's disease, or mild cognitive impairment (MCI).

[0235] This invention provides a method for improving an individual's immune function. As used herein, “immune function” refers to the body’s defense mechanisms against pathogens. Pathogens may include bacteria, viruses, fungi, protozoa, parasites, prions, and the like. Therefore, improved immune function may refer to a number of markers that are improved as a result of carrying out the methods of this invention. Biological markers indicating improved immune function may be selected from, but are not limited to, white blood cell count, cytokines, antibody types, antibody levels, complement system proteins, inflammatory markers, T cells, natural killer (NK) cell activity, phagocytic activity, and the like. Therefore, “improving immune function” is defined as improving or regulating any marker associated with improvement of the immune system, even partially.

[0236] In one embodiment, the present invention provides a method for improving immune function in an individual, and this method is This includes individuals performing at least one digital intervention from among sensory inhibition, sensory substitution, sensory integration, or a combination thereof.

[0237] In one embodiment, the present invention provides a method for increasing neural connectivity in an individual, and this method is This includes individuals implementing a digital therapeutic intervention plan that includes at least one digital intervention, which may involve sensory suppression, sensory substitution, sensory integration, or a combination thereof.

[0238] In one embodiment, at least one digital intervention is included in the digital therapeutic intervention plan. In one embodiment, a method for improving immune function includes a digital intervention comprising at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof. Examples of psychological, cognitive, and physical interventions have already been provided herein. In one embodiment, at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, extends over a period ranging from 1 second to 60 minutes. Other embodiments regarding duration have already been provided herein. Furthermore, embodiments regarding the length of the process, such as 1 day to 10 years, have already been provided herein.

[0239] In one embodiment, the present invention provides a method for improving immune function in an individual, the method comprising performing at least one digital intervention including sensory suppression. In one embodiment, the present invention provides a method for improving immune function in an individual, the method comprising performing at least one digital intervention including sensory substitution. In one embodiment, the present invention provides a method for improving immune function in an individual, the method comprising performing at least one digital intervention including sensory integration. As understood herein, sensory suppression, substitution, and integration can be used individually or in any combination to perform digital interventions. Personalization of an individual's digital therapeutic intervention plan is tailored to each individual, but general guiding principles can be used to design the intervention plan. As described below, digital intervention plans can be commonly available through multiple digital interventions using the three principles of sensory suppression, substitution, and integration, some based on cognitive interventions, psychological interventions, or a combination thereof.

[0240] In one embodiment, a method for improving immune function further includes an adaptation plan during the process of a digital therapeutic intervention plan. Receiving any of the data disclosed herein, Receiving updated data in accordance with at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof, Analyzing data and updated data using machine learning, artificial intelligence (AI), or statistical modeling, This includes generating updated digital therapeutic intervention plans for individuals based on the analysis of updated data.

[0241] Types of adaptations disclosed herein include, for example, the type of intervention, the sequence of interventions, the frequency of interventions, the intensity of interventions, the length of interventions, the difficulty of interventions, the sensory modal inputs used, the level of interaction, or combinations thereof.

[0242] In one embodiment, a method for improving immune function in an individual includes at least one cognitive intervention. In one embodiment, a method for increasing and improving immune function in an individual includes at least one psychological intervention. In one embodiment, a digital intervention includes at least one cognitive intervention and at least one psychological intervention. In one embodiment, a digital intervention includes at least one cognitive intervention, at least one psychological intervention, at least one physical intervention, or a combination thereof.

[0243] The digital interventions of the present invention provide methods for treating, preventing, or alleviating symptoms in individuals suffering from various diseases, but these methods can also be used by individuals who are otherwise not suffering from these diseases. For example, those who aim to increase general well-being by improving immune function. Maintaining a strong immune system provides a good foundation for maintaining an individual's health and well-being over a longer period of time. Therefore, these methods can be used as preventive measures, as well as for treating and / or alleviating symptoms.

[0244] In one embodiment, the present invention provides a method for treating, preventing, or alleviating symptoms in an individual suffering from an immune-related disorder. The general classification of immune-related disorders is autoimmune disorders and immunodeficiency disorders.Examples of autoimmune disorders include, but are not limited to, alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, autoimmune urticaria, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, dermatomyositis, discoid lupus erythematosus, epidermolysis bullosa acquisita, gestational pemphigoid, hidradenitis suppurativa, lichen planus, lichen sclerosus, linear IgA disease, localized scleroderma, psoriasis, pemphigus vulgaris, systemic scleroderma, vitiligo, autoimmune enteropathy, autoimmune hepatitis, celiac disease, Crohn's disease, pernicious anemia, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, rheumatic heart disease, Kawasaki disease, giant cell arteritis, Takayasu arteritis, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), leukocytoclastic vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, Goodpasture syndrome, IgA nephropathy, membranous nephropathy, lupus nephritis, primary sclerosing cholangitis, acute disseminated encephalomyelitis, acute motor axonal neuropathy, anti-NMDA receptor encephalitis, autoimmune encephalitis, Baló concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating diseases, Lambert-Eaton myasthenic syndrome, multiple sclerosis, myasthenia gravis, neuromyelitis optica / NMOSD, stiff-person syndrome, Sydenham chorea, undifferentiated connective tissue disease (UCTD), Addison's disease, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune polyendocrine syndrome type 1 (APS1), autoimmune polyendocrine syndrome type 2 (APS2), autoimmune polyendocrine syndrome type 3 (APS3), type 1 diabetes, Graves' disease, Hashimoto's thyroiditis, Ord's thyroiditis, Sjögren's syndrome, rheumatic lung disease, sarcoidosis, autoimmune hemolytic anemia, immune thrombocytopenia, thrombotic thrombocytopenic purpura, antiphospholipid antibody syndrome, paroxysmal nocturnal hemoglobinuria, autoimmune retinopathy, autoimmune uveitis, Cogan's syndrome, Graves' ophthalmopathy, Mooren ulcer, opsoclonus-myoclonus syndrome, optic neuritis, Susac syndrome, sympathetic ophthalmia, inclusion body myositis, myositis, autoimmune neuromyotonia, paraneoplastic cerebellar degeneration, and polymyositis.

[0245] Examples of immunodeficiency disorders include, but are not limited to, severe combined immunodeficiency (SCID), DiGeorge syndrome, hyperimmunoglobulin E syndrome (Job's syndrome), common variable immunodeficiency (CVID), chronic granulomatous disease (CGD), Wiskott-Aldrich syndrome (WAS), autoimmune lymphoproliferative syndrome (ALPS), hyper IgM syndrome, leukocyte adhesion deficiency (LAD), NF-κB essential modulator (NEMO) mutations, selective immunoglobulin A deficiency, X-linked agammaglobulinemia (XLA), X-linked lymphoproliferative disease (XLP), and ataxia telangiectasia.

[0246] Combination digital therapy for improving immune function The present invention provides a combination therapy for improving immune function, the therapy comprising administering at least one digital therapy and performing at least one non-digital medical intervention. In one embodiment, the combination therapy for improving immune function comprises administering at least one digital therapy and administering at least one pharmaceutical agent. As noted above, the term "combination" (or "combination method") is used to describe any intervention that includes at least one digital therapy intervention and at least one non-digital therapy intervention. Thus, for any method disclosed herein, a "single" method that utilizes only digital therapy interventions is used as being equally included within the "combination" intervention. Thus, all methods directed to improving immune function that utilize only digital interventions can be understood to be used in combination with the various non-digital interventions disclosed. One advantage of the present invention is its combination with known drug therapies, which helps to improve the results. In one embodiment, the combination method is for treating, preventing, or alleviating symptoms in an individual suffering from Parkinson's disease, Alzheimer's disease, or mild cognitive impairment (MCI).

[0247] In one embodiment, the present invention provides a method for improving immune function in an individual, the method comprising Individuals performing at least one digital intervention from sensory inhibition, sensory substitution, sensory integration, or a combination thereof, This includes administering at least one non-digital medical intervention before, during, or after at least one digital intervention, or a combination thereof.

[0248] In one embodiment, a combination method for improving immune function is intended to treat, prevent, or alleviate symptoms in an individual suffering from an immune-related disorder. Immune-related disorders are disclosed above.

[0249] In various embodiments, at least one non-digital medical intervention for a combination method to improve immune function is selected from pharmaceuticals, medical procedures, physiotherapy, psychotherapy, psychiatry, rehabilitation, lifestyle interventions, nutritional supplements, mineral supplements, and physical exercise.

[0250] In one embodiment, the pharmaceutical agent is selected from immunosuppressants, bioimmunotherapies, psychedelic drugs, and immune checkpoint inhibitors. In one embodiment, the immunosuppressant is selected from steroids, colchicine, hydroxychloroquine, sulfasalazine, dapsone, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, or a combination thereof. Examples of psychedelic drugs, but not limited to these, include LSD (lysergic acid diethylamide), psilocybin (magic mushroom), MDMA (ecstasy or Molly), DMT (dimethyltryptamine), peyote, ayahuasca, ketamine, mescaline, PCP (phencyclidine), and Salvia divinorum.

[0251] In one embodiment, the biological immunotherapy is selected from anakinra, canakinumab, rilonacept, infliximab, adalimumab, golimumab, etanercept, certolizumab, tocilizumab, sarilumab, eculizumab, rituximab, belimumab, abatacept, secukinumab, ixekizumab, brodalumab, guzerkumab, ustekinumab, dupixent, vedolizumab, tofacitinib, upadacitinib, baricitinib, mepolizumab, rezlizumab, benralizumab, or a combination thereof.

[0252] In one embodiment, the immune checkpoint inhibitor is selected from PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, TIGIT inhibitors, CD40 agonists, OX40 agonists, GITR agonists, IDO1 inhibitors, VISTA inhibitors, B7-H3 inhibitors, or combinations thereof. Examples of PD-1 inhibitors include, but are not limited to, pembrolizumab, nivolumab, and semiprimab. Examples of PD-L1 inhibitors include, but are not limited to, avelumab, atezolizumab, and durvalumab. Examples of CTLA-4 inhibitors include, but are not limited to, ipilimumab and tremelimumab. An example of a non-exclusive LAG-3 inhibitor is relatrimab. An example of a non-exclusive TIM-3 inhibitor is sabatrimab. Examples of TIGIT inhibitors include, but are not limited to, tiragolumab and domvanarimab. An example of a CD40 agonist that is not exhaustive is sericrerumab. An example of an OX40 agonist that is not exhaustive is utomirumab. An example of a GITR agonist that is not exhaustive is tiragolumab.

[0253] In one embodiment, the immune checkpoint inhibitor is selected from PD-1 inhibitors, pembrolizumab, nivolumab, cemiprimab, PD-L1 inhibitors, avelumab, atezolizumab, durvalumab, CTLA-4 inhibitors, ipilimumab, tremelimumab, LAG-3 inhibitors, leratrimab, TIM-3 inhibitors, sabatrimab, TIGIT inhibitors, tiragolumab, domvanarimab, CD40 agonists, sericrelumab, OX40 agonists, utomirumab, GITR agonists, tiragolumab, IDO1 inhibitors, VISTA inhibitors, B7-H3 inhibitors, or combinations thereof.

[0254] In one embodiment, the combination method is further configured so that the digital therapeutic intervention plan takes into account the individual's medication intake, drug regimen, and non-digital medical intervention schedule in order to achieve improved immune function.

[0255] Digital therapy to improve motor skills This invention provides a digital-based therapy for improving motor skills. Generally, “motor skills” refer to the ability to perform physical movements, such as manipulating objects with precision and coordination. These skills involve the integration of sensory information, muscle control, and cognitive processes to effectively perform specific movements. Motor skills can be broadly classified into two main types: gross motor skills and fine motor skills. Due to the physical nature of motor skills, the interventions associated with them are often referred to as “physical interventions.” As shown, the principles of sensory inhibition, substitution, and integration are applied to improving motor skills in a similar manner to those applied to increasing neural connectivity and improving immune function.

[0256] Therefore, “improving” motor skills means even minimal improvement or adjustment of at least one gross motor skill, at least one fine motor skill, or a combination thereof. The terms “improving” and “increasing” motor skills are used interchangeably. Typically, gross motor skills involve using large muscle groups to perform activities such as walking, running, jumping, and throwing. These skills are essential for activities that require whole-body strength, balance, and coordination. Fine motor skills involve using smaller muscle groups, particularly the muscles of the hands and fingers, to perform tasks that require dexterity, precision, and hand-eye coordination. Examples of fine motor skills include writing, drawing, tying shoelaces, and using tools.

[0257] In one embodiment, the present invention provides a method for improving an individual's motor skills on a digital platform. In one embodiment, the method is This includes an individual performing at least one digital intervention, which may involve a physical intervention based on sensory inhibition, sensory substitution, sensory integration, or a combination thereof.

[0258] In one embodiment, at least one digital intervention is included in the digital therapeutic intervention plan. In one embodiment, at least one digital intervention is performed at least partially on a personal electronic device.

[0259] In one embodiment, at least one physical intervention is selected from physiotherapy, voice therapy, speech therapy, swallowing therapy, breathing training, saliva and drooling therapy, chewing therapy, facial expression training, tremor management, mobility training, freeze and stiffness exercises, tapping training, limb agility exercises, volume-sustain-pitch training, training for gait freeze, motor function therapy, dance therapy, handwriting training, balance exercises, postural stability training, muscle training, stretching exercises, coordination training, metronome training, fine motor skills training, or a combination thereof.

[0260] All physical interventions utilize either sensory inhibition, sensory substitution, sensory integration, or a combination thereof on a digital platform. Therefore, sensory principles used for other purposes can be used for physical interventions in an equivalent manner. For example, voice therapy utilizes proprioception, which refers to the sense of body position and movement. Proprioceptive feedback is used to produce a specific pitch and adjust the quality of the voice in order to control the muscles involved in voice production, such as the vocal cords, diaphragm, and mouth. Thus, hearing (voice) and touch (proprioception) are two senses used together for voice therapy and training. Sensory principles employed for other methods of the present invention can be used equivalently for the purpose of improving motor skills.

[0261] In various embodiments, voice therapy includes digital versions of speech therapy techniques for patients suffering from language-related problems as a result of a medical condition, such as Parkinson's disease. As used herein, “voice therapy” also refers to “voice exercises.”

[0262] Voice exercises utilize the principles of sensory integration, deprivation, and substitution. In one embodiment, voice therapy includes amplitude training. In amplitude training, the patient's vocal volume is emphasized because, in some medical conditions, the voice becomes softer and weaker. First, a personal electronic device detects the normal and maximum vocal volume produced by the patient and establishes a starting point for the practice volume. The patient is then asked to say a specific syllable (e.g., "Aha," "Bha," "Boo"), word, or phrase, and to maintain a constant volume for a certain period of time while a digital platform (e.g., an app, software application) provides real-time feedback on how close the detected volume is to the required volume. With respect to individualization, the required volume level and duration can be increased / decreased based on the recorded initial level, as well as the patient's performance, and as the exercise progresses, the patient is continuously asked to maintain a higher volume for longer periods of time within a particular session and also between sessions. While speaking, the app provides feedback as follows: - A visual meter that shows the required volume and whether the patient is speaking above or below it. - Visual animations showing ascent or descent (e.g., ski lifts), - Auditory feedback to reach the desired volume and duration, - Tactile feedback to help reach the desired volume and duration.

[0263] Furthermore, the application may offer the patient the ability to record themselves and play back the recording for additional feedback. Various embodiments of voice therapy are implemented so that the exercise is constructed in a transition from being accompanied by visual and auditory and / or tactile feedback to auditory and / or tactile feedback alone (without visual feedback), i.e., using sensory principles. In corresponding ways, amplitude and pitch may be used for voice therapy, i.e., by adding a voice pitch modulus.

[0264] In one embodiment, the voice exercise includes reading comprehension training. The reading comprehension training is similar to the amplitude exercise, however, the patient is asked to read words, sentences, and / or paragraphs. The digital therapeutic intervention system, in various embodiments, focuses on measuring volume, modulation, and clarity. In one embodiment of the reading comprehension training, the patient is asked to read a list of words and then to recall them. In one embodiment, the patient is asked to read a list of words and then to recall them while blindfolded. In one embodiment, the words are not displayed on the screen but are played back, and the patient is also blindfolded while the words / sentences are introduced.

[0265] In one embodiment, speech therapy includes speech training. The speech training is implemented in a manner similar to amplitude exercise, however, the patient is cued and required to respond with speech. The cues can include a part of a conversation (e.g., "hi, how are you today?"), completion of a sentence (e.g., "what I love most about weekends is"), a question about an experience (e.g., "tell me about one good moment you experienced last week") or a question about information (e.g., "tell me the 4 directions on a map"). Further, the terms "input" and "cue" can be understood as interchangeable with each other from the perspective of sensory modalities. For example, when a sensory modality input or cue is provided by a personal electronic device.

[0266] As understood here, in one embodiment, "suppression" of a modality refers to suppression of the input of that modality. With respect to improving motor skills, sensory suppression includes reduction of at least one sensory modality input, at least in part. In one embodiment, the at least one sensory modality input is selected from vision, hearing, and touch. As understood here, in one embodiment, "substitution" with respect to a sensory modality refers to substitution of the input of that modality, for example, substituting vision with an auditory cue. In one embodiment, sensory substitution includes at least partial substitution of at least one sensory modality input by at least one other sensory modality input. In one embodiment, the at least partial substitution of at least one sensory modality input by at least one other sensory modality input is from vision to hearing and / or touch, from hearing to vision and / or touch, and from touch to vision and / or hearing.

[0267] With regard to improving motor skills, sensory integration includes a combination of at least two sensory modal inputs, at least partially. In one embodiment, the at least two sensory modalities are selected from visual, auditory, and tactile. In one embodiment, at least one digital intervention includes the individual interacting with a personal electronic device using any of the following means, selected from touch gestures, motion gestures, voice commands, text input, camera and media interaction, sensor-based interaction, or a combination thereof. Details of these means are provided above.

[0268] With regard to improving motor skills, at least one digital intervention will be implemented in one of the following forms: instructional videos, interactive videos including input and feedback from individuals, games, instructional prompts, question-and-answer surveys with feedback, virtual reality, augmented reality, or a combination thereof. Details of these forms are provided above.

[0269] In one embodiment, a method for improving motor skills is used to treat, prevent, or alleviate symptoms in an individual suffering from a motor disorder.

[0270] Examples of movement disorders include, but are not limited to, parkinsonism, ataxia, dystonia, tremor, chorea, tics, spasticity, gait disturbance, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Lewy body dementia (LBD), corticobasal degeneration, Huntington's disease, Friedreich's ataxia, idiopathic tremor, myoclonus, Tourette syndrome, restless legs syndrome, tardive dyskinesia, and Wilson's disease.

[0271] The digital maze of the present invention The “digital maze” of this invention relates to a maze that is performed in at least partially digital form. These are primarily used for digital therapeutic interventions and utilize “sensory principles,” that is, to perform digital interventions that include sensory inhibition, sensory substitution, sensory integration, or a combination thereof. Thus, digital mazes are typically performed on a system that includes a software application. Such a system includes a personal electronic device, but may also include any number of additional devices, as described.

[0272] Figures 1A-1B and 2A-2D show some examples of the digital mazes of the present invention. Figure 1A shows a screen show on a mobile phone application, arranged so that the user can see the floor, walls, and paintings on the walls. Figure 1B shows another digital maze where the exit point (also referred to as the “end point”) is in the field of view. The paintings on the walls can be used for a “recall” exercise after the user completes the digital maze. Such items placed within the digital maze can be used for memory exercises.

[0273] Figure 2A shows a bird's-eye view of six mazes of varying complexity. The user must navigate around obstacles (in this case, "walls" and "dead ends") to navigate from start to finish. Figure 2B shows further complexity in the series of digital mazes. Some digital mazes can be completed by the user along different paths. In various embodiments, the user must find the fastest path to the exit.

[0274] Figures 2C and 2D show different mazes that the user must navigate from start to finish. That is, the digital maze can be any structure. The digital maze can be a 3D structure, such as one that incorporates stairs requiring the user to move from one floor to another. Figure 2C shows a passage with several bends, the width of which changes along the path to the end. Figure 2D shows another digital maze with several paths that the user can take from start to finish. Figure 2D shows a rectangular obstacle placed in the center of the digital maze.

[0275] Figures 18A–18I show various screenshots from a digital therapeutic intervention platform, such as a mobile phone application. Figure 18A shows a progress chart for muscle relaxation. Any of the data described herein is graphically available on the digital interface. The display shows multiple scrollable tabs that the user can select, such as Badges, Personalization, and Sharing. The tabs are located at the bottom of the display, allowing the user to navigate to other options, such as Settings. Figure 18B shows an example of a personalized welcome screen. The screen shows what the daily activities are and provides an option for reminders to synchronize with the user's schedule. Figure 18C shows options within the "Explore tab." This gives the user further options for navigating various aspects of the digital therapeutic intervention plan, such as Education, Anxiety, Stress, Sleep Management, etc. Figure 18D shows another screenshot showing options in the form of tabs that provide the user with options for navigating the digital platform. Figure 18E shows a screenshot of a slide-rule feature where the user provides an answer to the question, "How do you feel today?". The user's answer is saved and used to plan and personalize the digital therapy. Other questions may be asked of the user in this manner. Figure 18F shows a screenshot where the user can select various symptoms they are experiencing, which may be done on a daily basis or on an intervention-by-intervention basis, to prepare the digital therapy platform to personalize the intervention accordingly. As with all data received by the software application (e.g., app), this may be saved and used for analysis and implementation purposes. Figure 18G shows one feature where the user can enter a "safe place" and select a variety of interventions, primarily to reduce stress and improve well-being.Figure 18H shows a screenshot of a welcome screen that allows users to choose whether they want to go to a "safe place" (to perform pre-intervention exercises) before their daily activities, helping them to be in a better mental state before starting their daily tasks.

[0276] Figure 18I shows a screenshot of the mobile phone application before the user completes the digital maze. The user is given information about the difficulty level, shown a schematic diagram of the maze, and informed of which sensory modes may be involved in navigating this particular digital maze. For example, the screenshot shows "Difficulty Level - Full Sight," meaning there is no clouding that would impair visual cues. In various embodiments, the digital maze is named, which provides another mode in which the user's memory can be incorporated into the learning experience.

[0277] In various embodiments, the digital mazes of the present invention include allocentric elements, egocentric elements, or a combination thereof. In an "allocentric" framework, direction and position are defined relative to external landmarks or a global coordinate system, independent of the observer's position or orientation. In the context of digital mazes, allocentric mazes are designed so that the layout and structure remain consistent regardless of the observer's viewpoint. The maze walls, paths, and landmarks are fixed in relation to each other, and the observer navigates by referring to these fixed features. For example, in a digital allocentric maze, a path might be described as "turn right at the T-junction" or "go straight until you reach the blue door." In contrast, an "egocentric" framework defines direction and position relative to the observer's own position and orientation. In a digital egocentric maze, the layout and structure of the maze may appear different depending on the observer's viewpoint. For example, if the observer turns to the left, the maze layout shifts accordingly, so that what was previously on the left is now on the right. Directions within an egocentric maze can be described in relation to the observer's current position and orientation. For example, directions may be given as "turn left" or "take two steps forward." Both embodiments can be incorporated into the digital maze of the present invention.

[0278] Methods and processes for navigating a digital maze are referred to as “computer implementation” methods. This refers to any method or process that uses a device to perform calculations. For example, a computer implementation method uses at least one electronic device capable of computation to perform tasks, manipulate data, process digital information, execute algorithms, or support software. A computer implementation method encompasses any functionality that depends on the computational power, storage capacity, and processing power of an electronic device, as described herein. A computer implementation method can execute instructions or algorithms by a processor or computing device. Instructions may be stored in computer-readable memory, such as random access memory (RAM), read-only memory (ROM), or storage devices such as hard drives or solid-state drives. In various embodiments, the methods of the present invention provide such computer implementation methods for performing various tasks, including a digital maze navigated by an individual, using a personal electronic device as a means.

[0279] In one embodiment, the present invention provides a computer implementation method for digital therapy for an individual, and this method is This includes presenting individuals with digital mazes on their personal electronic devices, Here, a personal electronic device provides sensory modal input selected from visual, auditory, tactile, or a combination thereof, enabling the individual to navigate a digital maze from a starting point to an ending point.

[0280] In one embodiment, the present invention is This provides a computer implementation method including personal navigation in a digital maze on a personal electronic device. Here, the individual uses sensory modal inputs selected from visual, auditory, tactile, or a combination thereof to complete a digital maze from a starting point to an ending point.

[0281] In one embodiment, the digital maze includes at least one obstacle selected from outer walls, inner walls, dead ends, objects, turns, interconnected paths, or combinations thereof. “Obstacle” is defined as any individual item included in the digital maze. In its simplest form, the maze may have no obstacles, and the individual must navigate from a starting point to an ending point. In some embodiments, the ending point is visible from the starting point. However, the digital maze can be of any shape, such as a winding passage, that the user must navigate from start to finish. Obstacles are generally placed in the digital maze to add complexity and / or difficulty to the maze, but as will become clear, the mere placement of objects in the maze is not the only factor that can add complexity and difficulty to the maze.

[0282] In one embodiment, sensory modal input is configured to assist an individual in completing a digital maze in the shortest time, shortest path, fewest obstacle collisions, or a combination thereof. For example, the user can view the maze in digital form (e.g., on a phone application) and swipe the phone to navigate through the maze. Furthermore, the user can receive auditory cues, for example, to inform the user how close they are to an obstacle. In some embodiments, each obstacle has its own unique sensory cue, such as vibration, melody, sound, etc. In one embodiment, the user is at least partially blindfolded while navigating the digital maze.

[0283] In one embodiment, the digital maze is presented to the individual for at least one repetition. In one embodiment, the digital maze is repetitioned 1 to 10 times. In one embodiment, the digital maze is repetitioned 1 to 50 times. In one embodiment, the digital maze is repetitioned 1 to 100 times. As the user becomes familiar with the maze, they become more proficient in completing it. The user can repeat mazes of the same difficulty level. Otherwise, the user can return to easier mazes, as described. One aspect of the digital maze is that it becomes more difficult for the user. Because the digital maze is used in digital therapeutic interventions, various embodiments add an element of progression through mazes of increasing difficulty.

[0284] In one embodiment, the method further includes generating a performance score upon completion of each digital maze by considering the time taken, the path taken, the number of obstacle collisions the individual had, or a combination thereof, when navigating at least one digital maze. Each maze may have different elements that need to be considered in order to generate a performance score. The examples provided for generating performance scores are for illustrative purposes only. Each performance score can be individualized according to the user's needs and requirements. For example, the performance score for a simple maze may be the same as the performance score for a difficult maze, but they may be weighted differently because the difficult maze was more challenging to complete. This is taken into consideration when evaluating an individual's overall performance in digital mazes. This is also particularly relevant in tracking an individual's progress through digital maze exercises and determining how to proceed next. In one embodiment, the method further includes generating a threshold performance score for a digital maze, above which the individual is no longer presented with a digital maze to complete. The examples provided for generating threshold performance scores are for illustrative purposes only. Each threshold performance score can be individualized according to the user's needs and requirements. Therefore, in various embodiments, the method includes repeating the digital maze until a threshold performance score is achieved. In one embodiment, even if the threshold performance score is achieved, the user may decide to continue repeating the digital maze. In one embodiment, the threshold performance score is modified to make the completion of the maze more difficult. For example, a simple maze can be made more difficult by increasing the threshold performance score. This means, for example, that the user must complete the maze faster or along a more efficient path.

[0285] In one embodiment, the method further comprises a personal electronic device providing a plurality of digital mazes, wherein for each digital maze of the plurality of digital mazes, an increase in sensory substitution is exhibited after completion of each digital maze and / or after a threshold performance score is achieved. Sensory substitution includes a personal electronic device providing at least partially substitution of at least one of the sensory modal inputs with at least one of the other sensory modal inputs.

[0286] In one embodiment, the method further includes repeating a plurality of the digital mazes, where, after the completion of each digital maze and / or once a threshold performance score is achieved, an increase in sensory substitution is exhibited for each subsequent digital maze of the plurality of digital mazes. Here, sensory substitution includes substitution by at least one other sensory modal input, where at least one partial substitution of sensory modal input is replaced by at least one other sensory modal input.

[0287] As mentioned above, and in one embodiment, the user may decide to repeat the digital maze even if they have completed it previously and / or achieved a threshold performance score.

[0288] In one embodiment, the method further includes one of the sensory modal inputs, From sight to hearing and / or touch, From hearing to sight and / or touch, This includes completely replacing the input with at least one other of the sensory modal inputs selected from tactile, visual, and / or auditory inputs.

[0289] In one embodiment, a personal electronic device is configured to perform navigation by touch gestures, motion gestures, voice commands, text input, camera and media interaction, sensor-based interaction, or a combination thereof. In one embodiment, touch gestures include tapping, swiping, scrolling, pinching, dragging, double tapping, or a combination thereof. In one embodiment, motion gestures include tilting, shaking, rotating, body movements, weaving, or a combination thereof.

[0290] As an individual navigates a maze, sensory cues may change to help them navigate it. In one embodiment, auditory input may be selected from changes in pitch, loudness, tone, melody, rhythm, music, or a combination thereof. For example, as the individual approaches a wall, the sound may become louder or its pitch may change. This applies not only when the individual approaches a wall, but also to moving obstacles that move towards or away from the individual. Auditory cues may change for each object, for example, a specific melodic phrase for each individual object. The individual may then be asked about the presence of various objects in the maze. For example, once the digital maze is completed, the user may be asked to identify the objects in the maze (and how many there were) using only auditory cues. As the individual progresses through the digital maze, incorporating sensory principles, the user will come to recognize specific sounds corresponding to specific objects. The user may then be asked to sketch the maze based on their navigation through it, using only auditory cues. The same principle applies to tactile cues. For example, specific haptic cues may correspond to different events in a digital maze, such as approaching an obstacle, colliding with an obstacle, or approaching the endpoint. Specific vibrations may correspond to these events in the digital maze, such as double vibrations, short vibrations, long vibrations, or specific vibration rhythms.

[0291] In one embodiment, the method further includes at least one additional device selected from a health monitoring system, medical device, haptic device, external speaker, headphones, virtual reality set, augmented reality glasses / device, biofeedback sensor, wearable activity tracker, smartphone, personal computing device, smart speaker, voice assistant, motion tracking sensor, virtual assistant system, internet hub, or a combination thereof, wherein at least one additional device is configured to transfer data between a person, a personal electronic device, or a combination thereof. In one embodiment, the personal electronic device, at least one additional device, or a combination thereof is configured to provide a sensory modal input. In one embodiment, the tactile input is vibration.

[0292] In one embodiment, for each digital maze, the individual completes multiple digital mazes of increasing difficulty after completion and / or achieving a threshold performance score. In one embodiment, the method further includes the personal electronic device providing multiple digital mazes of increasing difficulty for each digital maze, following completion and / or achieving a threshold performance score.

[0293] As can be understood, an individual can complete and repeat a single digital maze any number of times. That same digital maze can then be repeated using "sensory principles" such as sensory inhibition, sensory substitution, sensory integration, or a combination thereof. This applies to any maze of any difficulty. Therefore, after an individual completes a simple maze and goes through various levels of sensory inhibition / substitution / integration, the individual can then do the same with other digital mazes of increased difficulty. An individual can also return to any digital maze that has been previously attempted and / or completed. For example, if an individual has taken a break from performing digital interventions, they can return to an easier digital maze that was easy to complete.

[0294] In one embodiment, the method further includes a personal electronic device providing increased sensory substitutions for each digital maze of increasing difficulty, Here, sensory substitution includes a personal electronic device providing at least partially substitution of at least one of the sensory modal inputs with at least one of the other sensory modal inputs.

[0295] In one embodiment, the method further includes one of the sensory modal inputs, From sight to hearing and / or touch, From hearing to sight and / or touch, This includes completely replacing at least one other sensory modal input selected from tactile, visual, and / or auditory inputs.

[0296] Modifying the difficulty of a digital maze can occur in many forms. It is understood that the difficulty level of a particular maze depends on the individual navigating the digital maze. For example, different obstacles or different sensory alternatives will be more difficult for some individuals than for others. However, guiding principles can generally be used to design digital mazes to be increasingly difficult. In one embodiment, increasing the difficulty is achieved by randomly generating digital mazes of different structures, increasing the path length, increasing the number of turns, increasing the number of obstacles, diversifying the types of obstacles, decreasing the path width, incorporating time challenges, increasing performance thresholds, changing sensory modal inputs, adding interactive elements, incorporating distractions, incorporating tasks, incorporating moving obstacles, or a combination thereof. A "turn" refers to changing the direction of the path within the digital maze using, for example, walls or obstacles. "Diversifying the types of obstacles" refers to different types of obstacles, for example, placing more of one type of obstacle compared to another type of obstacle. Increasing the performance threshold means that individuals must complete the digital maze more effectively, in a shorter time, and with fewer collisions with obstacles. Modifying sensory modal inputs refers to using sensory principles to add complexity to the digital maze. For example, using clouding in the digital maze means that the user must rely on auditory / tactile cues rather than visual ones. Alternatively, auditory cues may be modified, and the user must decide how to proceed next in the maze given the modification. The digital maze can be made into a game where the user must interact with elements within the digital maze. For example, the user must reach a specific position in the digital maze before reaching the finish line. The user may be asked to interact with various elements within the maze. For example, the user may be instructed to "carry" an item at one point in the maze and move it to another location in the maze.In various embodiments, these interactive tasks may rely solely on auditory cues, while navigation within the maze is visual. For example, a task might require the user to pick up an object and place it on the opposite side of the maze, but the only cues the user receives about that object are a louder sound when the user approaches the object, a different sound when the user picks up the object, and another sound instructing the user to place the object in a specific location. These principles may be applicable to any configuration of a digital maze, and the examples provided herein are not intended to limit the scope. In various embodiments, a digital maze provides a platform for implementing sensory principles, primarily for digital interventions. A digital maze is designed to test and improve the user's memory. In this way, the user may be asked to recall elements experienced during navigation within the digital maze, such as portraits on a wall or the location of obstacles.

[0297] The digital interventions described herein may be designed as games, and the treatment plan may include gamification elements such as badges, scores, leaderboards, rankings, game currency, and similar elements, all of which stimulate the user's reward system, thereby resulting in the production and release of dopamine. This result is beneficial in several ways. It improves compliance with the digital intervention itself and with the treatment plan as a whole. It also has several therapeutic benefits. Increased dopamine can modulate the immune system. Furthermore, in some diseases such as Parkinson's disease, patients suffer from decreased dopamine in the brain, and many patients are actually treated with dopamine agonists, and the increase in dopamine in the brain induced by digital intervention may have therapeutic effects, either on its own or in combination with such drugs. In one embodiment, the method further includes gamification elements. In one embodiment, the gamification elements are selected from badges, scores, leaderboards, rankings, game currency, quests or missions, characters or avatars, virtual goods, social media features, experience points (XP), or a combination thereof.

[0298] In one embodiment, the digital maze includes 1 to 1,000,000,000 obstacles. In one embodiment, the digital maze includes 1 to 1,000,000 obstacles. In one embodiment, the digital maze includes 1 to 1,000 obstacles. In one embodiment, the digital maze includes 1 to 100 obstacles. In one embodiment, the digital maze includes 1 to 10 obstacles. In one embodiment, the digital maze includes 1 to 5 obstacles.

[0299] In one embodiment, the obstacle is stationary, moving, or a combination thereof. In one embodiment, the obstacle is stationary. In one embodiment, the method further includes providing instructions to the individual before, during, after, or a combination thereof, the digital maze.

[0300] The digital maze can be run by an individual on any number of platforms and on any number of devices, such as personal electronic devices. In one embodiment, the personal electronic device is selected from smartphones, tablets, wearable devices, smart TVs, computers, laptops, e-readers, game consoles, smartwatches, fitness trackers, portable media players, digital cameras, virtual reality (VR) headsets, augmented reality (AR) devices, portable GPS devices, portable Bluetooth devices, portable digital assistants, smart glasses and audio devices, or any combination thereof.

[0301] In one embodiment, the computer implementation method is a method for use in digital therapy. In one embodiment, the computer implementation method performs at least one digital therapy intervention. In one embodiment, the computer implementation method is for use in a digital therapy intervention plan. Thus, the use of the digital maze of the present invention is incorporated into any digital therapy intervention disclosed herein.

[0302] In one embodiment, the digital therapy includes at least one digital therapeutic intervention applied to an individual, which involves sensory inhibition, sensory substitution, sensory integration, or a combination thereof. Therefore, the sensory principles used to run the digital maze, and the implementation of sensory inhibition, sensory substitution, sensory integration, or a combination thereof, are understood to be disclosed elsewhere in this specification.

[0303] Digital Therapy System of the Present Invention The digital therapeutic interventions described herein are performed on a digital therapeutic system, which is outlined below in various embodiments.

[0304] In one embodiment, the present invention is A processor comprising at least one personal electronic device, wherein at least one personal electronic device includes an internal memory system, This specification provides a digital therapeutic system including a software application for a digital therapeutic intervention that implements the computer implementation method of this specification.

[0305] As understood herein, a “software application” is a program that runs on a device. In various embodiments, a “software application” is a computer program that performs a specific task or function on a device.

[0306] In one embodiment, the digital therapeutic intervention includes multiple intervention sessions. In one embodiment, the system further includes digitally stored instructions for the digital therapeutic intervention. Here, at least one processor is configured to execute digitally stored instructions, thereby allowing a software application to perform functions on a personal electronic device, and the software application, Receiving user input through multiple interactive elements, To process user input and execute multiple intervention sessions, data is transferred between the internal memory system and software applications. It is further configured to display a graphical user interface (GUI) related to digital therapeutic interventions on a personal electronic device.

[0307] In one embodiment, the system further includes at least one analytical tool based on machine learning, artificial intelligence (AI), statistical modeling, or a combination thereof, and is configured to analyze data for the analysis and personalization of digital therapeutic interventions.

[0308] In one embodiment, the system further includes an external storage system. In one embodiment, the system further includes at least one external storage system. Examples of external storage systems include databases, USB storage, network-attached storage (NAS), cloud servers, online repositories, or a combination thereof. In various embodiments, the analysis tool adjusts interventions, treatment content, and / or interaction styles according to individual requirements based on real-time or historical analysis of user data. In one embodiment, the machine learning tool employs a deep learning algorithm to predict user responses and pre-optimize treatment sessions. Deep learning methods are also incorporated in the methods disclosed herein.

[0309] In one embodiment, multiple interactive elements are selected from user commands, user selections, data inputs, or a combination thereof. In one embodiment, the GUI is presented to the user in a format selected from text, images, video, audio, or vibration, in response to information about the user's interactions and / or the software application. In one embodiment, the GUI adapts its presentation format based on the user's device type, accessibility settings, or past user interactions. In one embodiment, the system is further configured to perform multiple background tasks. Examples of multiple background tasks, but not limited to, include maintaining application functionality, data synchronization and updates, delivering notifications to the user, system monitoring, error logging, cache management, security checks, data encryption, or a combination thereof. In one embodiment, at least one processor is configured to ingest, transfer, analyze, or combine data selected from user interactions, user preferences, user demographics, user usage patterns, user feedback, timestamps, data from multiple intervention sessions, or a combination thereof. In one embodiment, the GUI is configured to adapt its presentation format based on the user's device type, accessibility settings, past user interactions, or a combination thereof.

[0310] In one embodiment, the system further includes at least one wireless network device configured to wirelessly transfer data. Examples of wireless network devices, but not limited to, include Wi-Fi adapters, cellular modems, Bluetooth modules, near-field communication chips (NFC), wireless local area network (LAN) cards, wireless routers, and wireless access points. In one embodiment, the system is further configured to perform digital therapeutic interventions in any of the following forms: instructional videos, interactive videos including input and feedback from individuals, games, instructional prompts, question-and-answer surveys with feedback, virtual reality, augmented reality, or a combination thereof.

[0311] In one embodiment, the system further includes at least one additional device selected from a health monitoring system, medical device, haptic device, external speaker, headphones, virtual reality set, augmented reality glasses / device, biofeedback sensor, wearable activity tracker, smartphone, personal computing device, smart speaker, voice assistant, motion tracking sensor, virtual assistant system, internet hub, or a combination thereof, wherein at least one additional device is configured to transfer data between a person, personal electronic device, or a combination thereof. In one embodiment, at least one additional device is a health monitoring system.

[0312] In one embodiment, the system is configured to transfer data between the system and at least one additional device to personalize digital therapeutic interventions. Thus, the system transmits / receives / captures / transfers data from at least one additional device or other health monitoring system for enhanced personalization and accuracy of treatment.

[0313] Digital Therapies for the Treatment of Neurodegenerative Diseases such as Alzheimer's Disease (AD) This invention relates to the field of digital therapy (DTx), which is primarily software-based and aims to provide care to patients.

[0314] Digital therapy digitizes already accepted disease management techniques, such as cognitive stimulation therapy (CST). Digital therapy provides non-pharmacological interventions, such as psychosocial interventions, which are effective in preventing, reducing, or treating non-cognitive symptoms. Similarly, rehabilitation interventions such as cognitive stimulation therapy, cognitive rehabilitation, physical exercise, and gait / balance training can improve cognition, function, stability, and / or quality of life for people with dementia. Cognitive abilities and functions such as attention, memory, executive function, planning, and perception are typical components targeted by digital therapy interventions.

[0315] The present invention provides a digital platform for performing at least one of the following actions for a disease or disorder: to treat, regulate, alleviate, improve, slow progression, delay onset, prevent exacerbation, or improve the quality of life of an individual suffering from a disorder. The terms “disease,” “disorder,” “condition,” “syndrome,” “illness,” “distressing illness,” “malfunction,” “pathological state,” and “disease” are used interchangeably in various embodiments as they relate to the functions performed by digital treatment.

[0316] In one embodiment, DTx is used to treat neurodegenerative diseases. Thus, and in some embodiments, at least two primary mechanisms (or modes) of action are used, which are complementary to one another. The first embodiment consists of digital interventions aimed at directly influencing the brain to improve spatial and linguistic memory and cognition and to increase synaptic connectivity. The second embodiment consists of digital interventions that modulate the immune system (through the application of a top-down approach) to improve the way in which the brain functions in protecting the brain from the adverse effects of neurodegenerative diseases. As will be described in detail below, each of these modes may be used on a standalone basis or in combination with specific drugs used to treat neurodegenerative diseases. In one embodiment, the digital therapy includes at least one cognitive intervention. In one embodiment, the digital therapy includes at least one psychological intervention. In one embodiment, the digital therapy includes at least one cognitive intervention and at least one psychological intervention. In one embodiment, the digital therapy includes at least one cognitive intervention, at least one psychological intervention, or a combination thereof. In summary, these interventions improve synaptic connectivity in the brain and enhance brain elasticity in patients with neurodegenerative diseases and other neurodegenerative diseases such as Parkinson's disease, as detailed herein. Digital interventions are ultimately expected to slow or halt cognitive decline associated with neurodegenerative diseases.

[0317] The specific protocols for digital interventions described herein are provided merely as exemplary embodiments and are not intended to limit the scope of the invention, as various alternative protocols can be designed based on the same underlying principles.

[0318] Digital interventions aimed at improving synaptic connectivity The digital interventions included in this mode act directly on the brain, improving synaptic connectivity and brain elasticity, and enhancing spatial and linguistic memory.

[0319] It should be noted that sensory and multisensory stimulation can effectively improve the pathology of neurodegenerative diseases (e.g., Alzheimer's disease (AD)), evoke memory, and improve cognition and behavior. Furthermore, digital therapies induce neural oscillations, enhance brain plasticity, and modulate regional cerebral blood flow. In addition, evidence is provided demonstrating neuroplasticity throughout aging and in the early stages of dementia. The data provided demonstrate that individuals with early-stage AD have the ability to relearn previously forgotten information or to improve cognitive abilities following cognition-focused interventions. Thus, the existence of compensatory processes is shown even when dementia-related pathology is present.

[0320] As demonstrated, reprogramming the brain through sensory surrogate devices and methods (including sonification, which is the conversion of data into sound signals that can be perceived by the human ear and interpreted by the brain) increases activation in specific brain regions, improves synaptic connectivity between the parietal region and the hippocampus (both associated with spatial and linguistic memory), and further improves synaptic connectivity between the peripheral visual navigation region (which plays a role in detecting landmarks and cues used for spatial navigation and processing) and other brain regions involved in spatial processing, including the posterior parietal cortex and hippocampus.

[0321] As described, visual deprivation (by blindfolding) results in rapid neuroplastic changes in visually impaired individuals, including the recruitment of peripheral visual navigation areas and the primary visual cortex for tactile and auditory processing.

[0322] The present invention thus includes digital interventions based on multidimensional sonification (integrating linguistic and spatial information and transmitting it through sound), which, in various embodiments, require the trainee to use both spatial and linguistic abilities while blindfolded. These interventions aim to promote neuroplasticity and increase synaptic connectivity and activity in areas specifically affected by neurodegenerative diseases such as AD, particularly in areas related to spatial cognition, memory, and language, thereby preventing or delaying disease-related disconnection and cognitive decline. Examples are presented throughout this specification.

[0323] The integrated maze, part of which is integrated with the TopoSpeech algorithm ("TopoSpeech maze") Cognitive training mazes that include auditory stimuli that play a role in conveying spatial information about the maze can activate brain regions associated with navigation and spatial cognition. Examples of such mazes include the Hebb-Williams maze and the Morris water maze. This invention includes a digital intervention aimed at treating patients with neurodegenerative diseases such as AD, and is based on these findings and other matters. Figures 1A–1B and 2A–2D include some examples of screenshots of digital mazes and drawings of mazes. Figure 1A shows a screenshot from a mobile phone application in which a user navigates a maze from a starting point to an ending point. In Figure 1A, the exit point is not visible, while the floor, walls, and drawings of the walls are visible. As the user navigates the maze, the exit point becomes visible in Figure 1B. As will become clear, the user navigating the maze uses visual and auditory cues. One method employed is to gradually reduce reliance on visually seeing the maze and increase reliance on auditory cues. In this way, the user will eventually navigate the maze of increasing complexity using only sound.

[0324] In addition to using a virtual version of a maze (or similar spatial task) with auditory stimuli, the present invention, in one of its embodiments, utilizes the "TopoSpeech" algorithm, a novel sensory alternative method for conveying spatial information to visually impaired and low-vision individuals through linguistic and auditory characteristics. In this algorithm, objects in space, such as bottles or laptops, are assigned names, their locations are represented through auditory characteristics, higher pitches indicate objects at higher positions, and temporal characteristics determine the horizontal axis.

[0325] To maximize outcomes in AD patients, digital interventions based on navigating a maze (or similar spatial task), combined with auditory stimuli (including, in some cases, the application of the TopoSpeech algorithm), should be operated on a blindfolded subject. As used herein, the subjects using or receiving digital therapeutic interventions are referred to in multiple ways. For example, “user” may also be referred to as “patient,” “individual,” “subject,” “participant,” or “recipient,” and can be understood interchangeably.

[0326] In one embodiment, the TopoSpeech maze is performed by a combination of all the elements described above, which is the integration of (x) spatial (non-verbal) information and (y) TopoSpeech (verbal) information regarding the maze, and is applied to a blindfolded subject using (z) sonification techniques and sensory substitution. To solve the maze, the trainee is expected to utilize both spatial and verbal cues, and thus use a combination of spatial and verbal skills, which are two of the most important brain functions impaired in AD patients (both of which are located in the hippocampus and connected brain structures). In various embodiments, the integration of the aforementioned elements facilitates multisensory integration and increases corticocortical connectivity in brain regions associated with Alzheimer's disease, such as the parietal region and hippocampus, which are involved in both spatial perception and memory.

[0327] The following Example 1 (also referred to herein as the “Aging Study” and “Study A”) illustrates several aspects of the benefits of the claimed invention. As part of the Aging Study, a mobile application with a sensory training program was used to target the cognitive abilities of older participants (55–60). Over a two-week period, the effects of digital egocentric navigation training were assessed, facilitated by the app (partially based on a Hebb-Williams maze combined with auditory stimulants and blindfolds). The study endpoints included, among other things, functional and structural connectivity of the brain, psychological well-being, and specific biomarkers. Other outcomes included, among other things, measuring the effects of interventions on hormones and antibodies related to the learning process and stress.

[0328] Multidimensional memory training Another embodiment of the present invention consists of a digital intervention that performs multidimensional memory training based on a similar principle. One example of this type of digital intervention is memory training that utilizes the TopoSpeech algorithm, in which the subject must attempt to remember the order of words previously recited to the subject and their spatial "positions". In various embodiments, this type of digital intervention is performed on a blindfolded subject.

[0329] As described, the digital intervention platform offers many different types of interventions that can be used individually or in combination to achieve positive outcomes.

[0330] In some aspects of the present invention, the digital interventions described herein may be administered in conjunction with other types of sensory stimulation, such as tactile stimulation (e.g., by rotating a telephone), which will be integrated within the DTx.

[0331] Digital interventions aimed at regulating the immune system A strong link exists between the immune system and neurodegenerative diseases (including Alzheimer's disease). The underlying mechanisms by which digital interventions influence Alzheimer's disease will, as will become clear, be applicable to other neurodegenerative diseases as well.

[0332] In one aspect, the immune system plays a significant role in the clearance of beta-amyloid plaques in the brain, which, as described above, is known to disrupt regular brain activity and worsen the symptoms of Alzheimer's disease (AD). In another aspect, the clearance process is achieved by phagocytosis, where immune cells known as phagocytic cells, including microglia, infiltrate the brain and remove harmful agents, including beta-amyloid plaques. In AD, the immune system and the brain interact in a complex and dynamic manner, which can have both beneficial and detrimental effects on disease progression. On the one hand, the immune system plays a crucial role in clearing beta-amyloid plaques from the brain, while on the other hand, chronic activation of the immune system can cause neuroinflammation, which is associated with neuronal damage and cognitive decline in AD.

[0333] Neuroinflammation in AD is partly driven by the activation of microglia and other immune cells in the brain. These cells release pro-inflammatory molecules such as cytokines and chemokines, which can attract more immune cells to the site of injury and promote further inflammation. Over time, this chronic neuroinflammation can lead to the accumulation of neurotoxic molecules as well as synapse and neuronal loss, contributing to the cognitive decline seen in AD. Figure 3 shows some schematic examples of the related mechanisms involved.

[0334] Referring to Figure 3, various pathways are shown, where digital therapy positively impacts various processes and indicators. Digital therapy has been shown to reduce neuroinflammation, norepinephrine and adrenaline, glucocorticoids, and pro-inflammatory cytokines. As shown throughout, digital interventions enhance synaptic connectivity and neuroplasticity and / or modulate the immune system.

[0335] Immunotherapy enhances the effectiveness of phagocytic cells in clearing beta-amyloid plaques and reducing neuroinflammation. Immunotherapy is a relatively new class of medicines that treat diseases by modulating the patient's own immune system to achieve an optimal response to the disease they are suffering from.

[0336] Immunotherapy, specifically immune checkpoint inhibitors (ICIs), is a promising approach to treating Alzheimer's disease (AD) by modulating the immune system and enhancing its ability to clear beta-amyloid plaques from the brain. Immune checkpoint inhibitors are a class of drugs that inhibit the activity of molecules that weaken the immune response, such as programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). By blocking these molecules, immune checkpoint inhibitors stimulate the immune system and enhance its ability to clear beta-amyloid plaques from the brain. Furthermore, immune checkpoint inhibitors can reduce neuroinflammation, a characteristic of AD, by inhibiting the activity of inflammatory immune cells.

[0337] By enhancing the peripheral immune system, T cell activity can be increased, resulting in increased IFN-γ availability, which activates the choroid plexus (CP) epithelium to express leukocyte chemotactic molecules. The enhanced ability of the CP to express these molecules supports the recruitment of monocyte-derived macrophages and regulatory T cells to the brain. Monocyte-derived macrophages can exert multiple effects, directly and indirectly, including suppression of the brain's inflammatory environment through local IL-10 production, as well as promotion of amyloid-beta oligomer and plaque removal by expressing intrinsic scavenger receptors (e.g., MSR1). Such immunomodulation leads to enhanced neuronal survival, synaptic rescue, and a more supportive environment for brain function. These findings have important implications for the development of novel therapeutic strategies to prevent or treat Alzheimer's disease by targeting the peripheral immune system, potentially offering less invasive and more effective approaches to combat this devastating condition.

[0338] It should be noted that neuroendocrine imbalances caused by physiological and psychological stressors, and the resulting pro-inflammatory profile, can adversely affect the immune response and potentially impair the success of immunotherapy and exacerbate the potential toxicity of immunotherapy drugs. Therefore, by restoring the correct neuroendocrine balance, patients may be able to respond better to these medications, and their overall effectiveness (i.e., both efficacy and safety) may increase.

[0339] Apart from the effects of stress on the immune system (and relatedly, on the effectiveness of immunotherapy), stress can directly influence the progression of neurodegenerative diseases such as Alzheimer's disease (AD). In many cases, individuals with Alzheimer's disease (AD) have elevated levels of chronic stress-mediated factors such as cortisol and norepinephrine. These stress-mediated factors, along with the pro-inflammatory agonists they produce, can induce the activation of microglia, which, as described above, play a significant role in the pathogenesis of AD and can induce the release of pro-inflammatory cytokines in the brain. This can lead to neuroinflammation, which in turn results in neurotoxicity, exacerbating the neurodegenerative process and the symptoms of AD. Furthermore, corticosteroids impair the entry of peripheral immunomodulatory cells into the brain, which is essential in restoring homeostasis and preventing stress-induced psychotic states (see Figure 3).

[0340] Considering the foregoing, the digital interventions of the present invention help induce psychophysiological effects. As shown herein, various digital interventions reduce stress and induce psychophysiological effects, thereby promoting the restoration of neuroendocrine and neuroimmunological balance in AD patients, and thereby delaying disease progression. These embodiments, as well as other studies showing the detrimental effects of stress-mediating factors on brain structure and their contribution to neurodegeneration, provide evidence that by implementing the digital interventions included in this mode to reduce stress in AD patients, the patient's condition is significantly improved in at least one of the many indicators used to define improvement. The digital interventions included in this mode of the present invention facilitate the restoration of neuroendocrine and neuroimmunological balance (supported by a decrease in IL-6 and an increase in CD4+ T cell and IFN-γ levels) and a reduction in neuroinflammation. Furthermore, these interventions reduce AD-specific distress and improve the patient's quality of life (see Figure 3).

[0341] Accordingly, this mode of the present invention includes apparatus, systems, and methods for treating AD patients through digital interventions that reduce stress and modulate the immune system. The digital interventions are designed to modulate specific brain regions such as the pituitary gland and hypothalamus, thereby reducing the activation of the hypothalamic-pituitary-adrenal (HPA) axis. This, in turn, results in a decrease in the secretion of stress-mediating factors, including glucocorticoids (such as cortisol), from the adrenal cortex. Furthermore, the digital interventions also reduce the activation of the sympathetic nervous system (SNS), which results in a decrease in the secretion of adrenergic factors such as adrenaline from the adrenal medulla and noradrenaline from sympathetic nerve endings. This helps to achieve neuroendocrine balance.

[0342] Some forms of digital intervention utilize immersive, body-based interventions that leverage the integration of sensory and multisensory stimuli (unique combinations of two or more senses) to allow the subject to experience those stimuli as embodied in their own body.

[0343] Combination with drugs As described above, the types of digital interventions considered herein may be used alone or in combination with pharmaceutical agents. Generally, adjunct pharmaceuticals are supplemental therapeutic agents used in conjunction with primary treatments to optimize effects or address specific aspects of a medical condition, often improving the overall therapeutic outcome. The present invention provides a selection of adjunct pharmaceutical agents, which are referred to separately as “non-digital medical interventions.” As will become clear, any therapeutic agent that achieves this objective in combination with the digital treatments of the present invention is considered to be within the scope of the invention. For example, a digital therapeutic intervention for neurodegenerative diseases may be used in combination with an adjunct pharmaceutical agent for neurodegenerative diseases. In one embodiment, a digital therapeutic intervention for improving the immune system may be used in combination with an adjunct pharmaceutical agent for improving immunity. As will be understood, any combination of a digital treatment and other non-digital interventions is considered to be within the scope of the invention.

[0344] In addition to immunotherapy, another type of agent that may synergistically interact with the digital interventions included in the present invention, as discussed above, is a drug that targets neuroplasticity, including through NMDA-mediated mechanisms. Such drugs are expected to provide the optimal biochemical balance necessary for neuroplasticity, which can be enriched by cognitive tasks that promote the development of synaptic connections related to spatial ability, memory, and other cognitive functions. Furthermore, certain digital interventions may facilitate the reequilibrium of the immune system, thereby further amplifying the effects of such drugs.

[0345] Drugs such as cholinesterase inhibitors or acetylcholinesterase inhibitors ("AChE inhibitors") are also implemented in combination with digital therapies. These drugs act by inhibiting the acetylcholinesterase enzyme, which is involved in the breakdown of the acetylcholine neurotransmitter, thereby increasing the level of this enzyme in nerve synapses. Acetylcholine plays a role in the peripheral and central nervous systems and is involved in memory and learning processes. In many cases, patients with AD have reduced levels of this neurotransmitter, and the neural pathways in the brain that utilize it are impaired, which contributes to cognitive impairment. By increasing acetylcholine levels, AChE inhibitors can help improve cognitive function and slow the progression of AD. The combination of digital interventions and AChE inhibitors can produce synergistic effects and significantly improve the patient's condition.

[0346] Anti-amyloid beta drugs (e.g., the humanized monoclonal antibody recanemab) can be combined with the digital interventions described herein.

[0347] Digital interventions, in combination with recanemab, act through at least two pathways. The first is through the direct effects of these therapeutic interventions on the brain, thereby improving synaptic connectivity and neural plasticity. Structural and functional changes related to the hippocampus and default mode network (DMN) are known to underlie age-related cognitive decline and are associated with Aβ accumulation. Examples demonstrate improved connectivity in these areas after training. Therefore, digital interventions can work with recanemab, potentially clearing existing plaque, enhancing connectivity in these areas, and improving cognitive and functional status.

[0348] A second pathway by which the digital interventions described herein can act in conjunction with recanemab is by restoring neuroimmunological balance and reducing neuroinflammation. The digital interventions described herein have shown to reduce depression and stress scores, reduce chronic inflammation, reduce pro-inflammatory cytokines, and prevent further neurodegeneration.

[0349] Donanemab is another example. It is an immunoglobulin G1 monoclonal antibody directed against the N-terminal cleavage form of β-amyloid, which is insoluble, modified, and present only in brain amyloid plaques. Donanemab binds to the N-terminal cleavage form of β-amyloid and helps remove the plaque through microglia-mediated phagocytosis.

[0350] In combination with recanemab, the digital interventions described herein can act in conjunction with donanemab and any other relevant anti-amyloid beta agents via the same pathway as described above.

[0351] SAGE-718 is an analogue of the neurosteroid 24S-hydroxycholesterol, which acts as a positive allosteric modulator of NMDA receptors. Administration of SAGE-718 showed improvements in executive function, learning, and memory, which is consistent with the results provided in the examples and shows increased connectivity between memory-related areas of the medial temporal lobe (MTL) and frontal areas of executive working memory.

[0352] Semolinemab is a humanized monoclonal IgG4 antibody against tau that targets the N-terminal domain of tau, binding to all known isoforms of full-length tau and affecting its binding and recognition.

[0353] In addition to the specific types of pharmaceuticals mentioned above, the DTx described and claimed as part of the present invention may act synergistically with other types of disease-modifying drugs for AD, whether or not they are approved as of the date herein.

[0354] While each mode of the present invention can be used individually, they can also be used in conjunction to produce synergistic effects. The unique digital interventions described and claimed as part of the present invention can also be combined with other computer-based cognitive training programs (e.g., exercises targeting memory, attention, and other cognitive domains) that help improve cognitive function in patients with AD. Overall, combinations of different digital interventions and treatments for AD may provide a more comprehensive and effective approach to managing the disease and improving patient outcomes.

[0355] In various embodiments, digital interventions are administered through the operation of a software application and may be delivered via any screen connected to the Internet (including, but not limited to, mobile phones, PCs, TVs, AR glasses, VR headsets, smartwatches, or other wearable devices) and / or any acoustic device connected to the Internet (including, but not limited to, headsets, speakers) and / or any connected haptic device capable of generating tactile sensations such as heat, cold, vibration, or pressure (e.g., bracelets, watches, rings, sleeves, belts, wristbands, vests, etc.) and / or any odor-emitting device and / or any other sensory stimulation device.

[0356] The system may also include interfaces that enable connection to a variety of wearables, including smartwatches and bracelets without limitation, and body-mounted sensors, including scalp, finger, and earlobe sensors without limitation, and other devices capable of monitoring activity and detecting various measurements of health and other information about the user's body, such as measurements related to temperature, heart rate (pulse), respiratory rate, heart rhythm, heart rate variability and electrical activity, blood glucose levels, muscle tone, sweat gland activity, sleep quality and electroencephalogram, as well as measurements of the user's physical activity (including steps, calories burned, etc.). Furthermore, the system tracks and compiles patient-reported outcome measures. Such data may be used to personalize and optimize digital components (e.g., by methods similar to biofeedback) while the digital components are being applied to the user, and also function as outcome measures.

[0357] Users can communicate with the application via a speech recognition system (SRS), via a tapping / movable vibrating wristband (VWB), or by writing on the screen during or after the completion of a digital intervention. The system can assess the participant's cognitive level and personalize the digital intervention to that level. The system can continuously collect user data and inputs to improve and personalize the digital therapeutic components for individual users, and can continuously improve its general operation (while using AI tools among others). Thus, the system described herein also functions as a data generation device. Continuous operation of the system is expected to result in the creation of a constantly expanding and improving database that can be used for a variety of purposes, including the development of individually adapted protocols for combination treatments.

[0358] detection The methods described for treating AD via digital tools can also be used as methods for diagnosing AD, alongside other existing methods for detecting AD. This can be done by using these digital interventions to test and assess participants' cognitive abilities and by detecting disruptions in multisensory integration as markers of AD that other methods might miss. For example, if a participant's performance on the TopoSpeech Maze declines over time, it may indicate a decline in spatial cognition and serve as a marker of AD. Similarly, the digital interventions described above may be effective for memory tests.

[0359] Conditioning In one embodiment, the method described herein further includes conditioning. As used herein, “conditioning” (or “conditioning stimulus”) refers to the process of associating a particular cue or stimulus with the administration of a drug or pharmaceutical in order to promote a positive effect or outcome. Conditioning may be carried out using sensory modal inputs. These sensory modal inputs are selected from visual, auditory, tactile, gustatory, olfactory, proprioceptive, and vestibular sensations. Thus, and in various embodiments, the digital method disclosed herein further includes a conditioned stimulus linked to a particular drug.

[0360] Another aspect of the present invention includes methods for conditioning a patient's brain to enable the patient to enjoy the benefits of a DTx component between and between treatment sessions, thereby making its medicinal effects more prolonged. These methods are based on the paradigms of Pavlovian classical conditioning and operant conditioning, and have been used, for example, to demonstrate that associating morphine with a neutral olfactory stimulus resulted in a morphine-like conditioned analgesic response to that olfactory stimulus. Based on a similar principle, the present invention includes methods for pairing a digital therapeutic component (unconditioned stimulus) with a “conditioned stimulus” so that the brain eventually responds to the conditioned stimulus in a manner similar to how it responds to DTx. This enables the patient to enjoy the positive effects of DTx, at least to some extent, simply by administering the conditioned stimulus. The pairing and conditioning methods described above are particularly useful given the underlying challenges in compliance with digital therapeutics.

[0361] In one embodiment, at least one digital intervention is administered with a conditioned stimulus selected from visual, auditory, tactile, or a combination thereof. In one embodiment, a pharmaceutical agent, at least one digital intervention, or a combination thereof is administered with a conditioned stimulus selected from visual, auditory, tactile, or a combination thereof. The conditioned stimuli of the digital therapeutic intervention and the conditioned stimuli of the pharmaceutical agent may be the same or different.

[0362] To ensure a conditioning effect, at least some digital training and stimuli will be accompanied by a distinct “conditioning stimulus.” For example, a fixed auditory theme (with slight variations), a distinct taste or smell integrated into the digital component, or a multisensory theme ("MST"), i.e., a specific combination of sound, vibration, and visual, or any other combination of sensory stimuli. The conditioning stimulus, or some aspects thereof, may be individualized for each user. The conditioning stimulus becomes associated in the user’s mind with the positive effect of the digital treatment.

[0363] In a mode of the present invention based on a combination of DTx and a drug, conditioning may also be used such that the DTx (or a conditioned stimulus linked to the DTx) gradually acquires some of the physiological effects of the drug, thereby enhancing the effectiveness of the digital component.

[0364] Therefore, the pairing here is between the digital therapeutic component (or the “conditioning stimulus” paired with it (see above)) and the drug component, thereby conditioning the brain to respond to the digital therapeutic component in a manner similar to how it responds to the drug. While the digital therapies described herein can generally be expected to have positive effects on patients, the pairing and conditioning methods described above can lead to increased adherence to and effectiveness of such digital therapies. This can ultimately facilitate an increase in the use of the digital component in the treatment and a simultaneous decrease in the weight of the drug component. In some cases, this may even make it possible to use the digital therapeutic component as a substitute for the drug or during drug intake (resulting in a longer-lasting medicinal effect of the drug). Reducing the dosage of the drug component reduces its side effects, as well as drug tolerance and associated user dependence.

[0365] In various embodiments, the conditioning effect acts in relation to a particular drug. Generally speaking, the stronger and / or faster the relief provided by the drug, the easier it is to create conditioning between the digital intervention and the drug.

[0366] Digital interventions delivered to patients via software applications (i.e., any of the digital interventions disclosed herein) may be continuously modified to minimize fatigue effects and maximize compliance with and effectiveness of the digital components. However, to ensure conditioning effects, at least some of the digital therapeutic training sessions and stimuli will be accompanied by a clear “conditioning stimulus.” The conditioning stimulus will be linked in the user’s mind to the positive effects of the treatment.

[0367] In some modes of operating the methods described herein, there will be additional steps that are performed before or in conjunction with drug administration and digital intervention, designed to produce an adrenaline boost or emotional arousal in the patient. For illustrative purposes, a patient may be prompted via a digital application that involves 3D sound and confronting dangerous stimuli (e.g., a lion or a torrent) to listen to a three-minute adventure training. By using such (or other) adrenaline boosters, the conditioning process is enhanced because adrenaline strengthens associative and learning processes in the brain.

[0368] Some embodiments of the present invention may also utilize the following (or other) methods of operational coupling. Since conditioning is stronger the clearer, time-synchronized perceptual causality between a conditioned stimulus (DTx) and an unconditioned stimulus (drug), stronger coupling can be established by implementing a technical protocol to strengthen the association, enforce the requirement to use a digital intervention, and enable the drug to be taken immediately thereafter. For explanatory purposes only, such a protocol may consist of: (1) the requirement to scan the tablet packaging (scanning a designated sticker on the digital drug amplifier on the packaging) to release the tablet / dosage / order instructions for the current treatment session. This may be artificially induced, for example, when taking multiple pills, even if the order / sequence is not medically important. It is also possible to use a dedicated pill packaging with a Bluetooth-operated lock, which requires scanning a designated sticker to unlock the box and allow access to the pills. (2) Scanning the pill packaging triggers a branded AR (augmented reality) holographic animation that appears to emerge from the package, accompanied by instructions for the pill / dosage / order for the current treatment session, thereby creating a visual association between the DTx and the drug. This visualization may be further designed to be used to create associations with specific visual stimuli (e.g., via VR) administered as part of the DTx.

[0369] In various embodiments, conditioning includes at least: 1) associating a digital intervention with a drug (so that using the digital intervention induces some of the drug's benefits without actually taking it); and 2) associating a digital intervention with a conditioned stimulus (so that using the stimulus induces the benefits of the digital intervention).

[0370] In one embodiment, at least one digital intervention is administered with a conditioned stimulus selected from visual, auditory, tactile, or a combination thereof. In one embodiment, at least one digital intervention, at least one non-digital intervention, or a combination thereof is administered with a conditioned stimulus selected from visual, auditory, tactile, or a combination thereof.

[0371] Parkinson's disease (PD) and digital therapy In the various embodiments described herein, references to individual diseases are made when the principles of a particular treatment are applicable to a broader group of diseases. It is understood that guiding principles outlining effective treatments for neurodegenerative diseases are generally applicable to other neurodegenerative diseases as well. Therefore, although not explicitly stated, when a treatment plan for Alzheimer's disease is referred to, for example, it is understood that other corresponding treatments are applicable to other neurodegenerative diseases.

[0372] Multiple pieces of evidence indicate that immune system dysfunction and neuroconnectivity play a role in Parkinson's disease (PD); this evidence includes clinical and genetic linkages between autoimmune disorders and PD, impaired cellular and humoral immune responses in PD, imaging evidence of inflammatory cell activation, and evidence of immunodysregulation in experimental models of PD. Many adjunctive pharmaceuticals and non-digital medical interventions can be used in conjunction with the digital interventions described herein.

[0373] For example, a central defect in Parkinson's disease (PD) is dopamine depletion from the basal ganglia. This leads to a major disruption in connectivity to the thalamus and motor cortex, resulting in the classic Parkinsonian signs of hypomotoria and rigidity.

[0374] Various therapeutic interventions, including medications, surgery, and rehabilitation, can effectively alleviate the symptoms of Parkinson's disease (PD). Among these, levodopa / carbidopa, a combination drug designed to increase dopamine levels in the brain, is the most commonly prescribed for PD. Thus, such drug combinations, when combined with digital therapies, have been shown to be effective against PD.

[0375] Levodopa functions as a precursor to dopamine and is converted in the brain. Simultaneously, carbidopa, which acts as a dopamine decarboxylase inhibitor, inhibits the peripheral conversion of levodopa to dopamine, thereby making it easier for more levodopa to cross the blood-brain barrier (BBB). Once converted to dopamine, it activates postsynaptic dopaminergic receptors, compensating for reduced endogenous dopamine levels.

[0376] Levodopa is an effective agent for controlling the motor symptoms of Parkinson's disease (PD), but it also requires the most frequent doses and is associated with the greatest risk of dopaminergic motor complications such as "wearing off" and dyskinesia. (Motor complications affect approximately 40% of Parkinson's disease (PD) patients more than 5 years after levodopa therapy).

[0377] In selected cases, initial treatment with dopamine agonists (DAs), monoamine oxidase B (MAO B) inhibitors, or amantadine is a reasonable alternative to early levodopa. Most such patients progress to requiring levodopa within a few years.

[0378] Dopamine agonists act by directly stimulating dopamine receptors in the brain. Initiating treatment with dopamine agonist monotherapy is currently recommended in younger patients to delay levodopa treatment.

[0379] MAO inhibitors work by blocking monoamine oxidase enzymes, which break down different types of neurotransmitters, including dopamine. MAO-B inhibitors inhibit the breakdown of dopamine, thereby increasing its available levels. MAO-B inhibitors may be used as early monotherapy or as an add-on to other medications, including levodopa, to reduce motor variability.

[0380] Amantadine is an antiviral agent with mild antiparkinsonian activity. The mechanism of action of amantadine in PD is uncertain, but it is known to increase dopamine release, inhibit dopamine reuptake, stimulate dopamine receptors, and possibly exert central anticholinergic effects. Amantadine monotherapy is an early alternative to levodopa in younger patients at risk of dyskinesia, particularly when tremors are prominent. Apart from its use as monotherapy, amantadine may be useful in managing levodopa-induced dyskinesia and "off" time in more advanced PD patients.

[0381] Patients with Parkinson's disease (PD) who experience motor complications that impair their quality of life can benefit from device-assisted interventions, including deep brain stimulation (DBS). DBS is the most frequently performed surgical procedure for treating PD. There are two main targets for reducing motor variability and dyskinesia associated with advanced PD: the subthalamic nucleus (STN) or the internal globus pallidus (GPi).

[0382] The procedure for DBS involves stereotactic neurosurgery for unilateral or bilateral electrode placement, which is connected to a pulse generator implanted in the chest wall. When activated, the pulse generator delivers high-frequency electrical stimulation to a specific target (GPi or STN).

[0383] DBS for motor complications of Parkinson's disease (PD) works in the following hypothetical way: Two downstream physiological effects of characteristic cytodegeneration of the substantia nigra and the corresponding loss of dopamine production are excessive GPi excitation of the spondylotropin (STN) and excessive GPi inhibition of the thalamus. These, in turn, lead to a decrease in thalamocortical activity, which is thought to mediate akinesia and rigidity. High-frequency DBS suppresses neural activity and also activates efferent fiber pathways leaving targeted nuclei.

[0384] The effects of digital interventions on Parkinson's disease The interventions described in detail above can benefit patients with Parkinson's disease (PD), either on the basis of PD alone or in combination with various medications.

[0385] Further analysis of Study A (see Example 1) described above revealed that multisensory psychocognitive training shows promise in enhancing the integrity of the basal ganglia-thalamocortical circuit.

[0386]

[0387] Figures 9A and 9B show results demonstrating increased connectivity between the ventrolateral thalamus (VTL) and the premotor cortex after training, and results showing a correlation between post-training VTL / premotor cortex connectivity and the time spent on training.

[0388] Figures 9C–9F show improved crosstalk between the frontal region (BA9) and the basal ganglia (GPi). GPi is one of the DBS targets described above and also shows improved connectivity within the basal ganglia network and with the somatosensory system.

[0389] Additional aspects include the impact of the digital interventions described herein on depression scores and the enhancement of connectivity in brain regions associated with depression and immune function, which are detailed in the description of Study A above (see also Study B and Example 2 for other beneficial psychological effects of depression scores and the interventions). These effects can significantly contribute to changes in well-being and disease progression in PD patients. Depression is prevalent among individuals with PD and negatively impacts motor function and overall quality of life.

[0390] In this specification, the use of the interventions described above demonstrates the ability to restore immune system balance or, in other ways, improve various immune system markers and indicators. By integrating psychological modules, including components of CBT, with multisensory training, the aim is to enhance connectivity in brain regions known to alter in both PD and depression. This holistic approach can synergistically benefit PD symptoms, thereby improving the overall functioning, mood, and quality of life of the affected individual.

[0391] Combination of digital therapy and drug therapy Dopaminergic therapy is central to the pharmacological treatment of Parkinson's disease (PD). These drugs have previously been shown to increase dopamine levels or act as agonists on dopamine receptors, modulating functional connectivity in the basal ganglia-thalamocortical circuit. Since the digital interventions described herein have been shown to enhance functional connectivity in this circuit, combining them with pharmacological treatments may produce synergistic effects.

[0392] By combining the intervention of the present invention with dopaminergic drugs such as levodopa, their efficacy is enhanced, leading to lower doses and less frequent dose changes, and reducing side effects.

[0393] Alpha-synuclein is a protein abundant in dopamine-producing neurons. In Parkinson's disease (PD), alpha-synuclein misfolds and aggregates into clumps called Louis bodies, which are intracellular inclusions that are a pathological feature of PD. Alpha-synuclein aggregates disrupt dopaminergic transmission and induce presynaptic and postsynaptic dysfunction. The immune response to alpha-synuclein misfolding contributes to disease progression, and the presence of early inflammation occurring before alpha-synuclein deposition and diffusion in experimental models and PD patients suggests a mechanistic link between inflammation and synaptic dysfunction. Examples, though not limited to these, include prazinezumab and buntanetap.

[0394] These alpha-synuclein-targeting treatments can be combined with the interventions described herein to achieve better outcomes for PD patients or other neurodegenerative diseases.

[0395] Examples Example 1 The effects of digital health methods on subjective cognitive decline (SCD) and other neurodegenerative conditions.

[0396] Two studies conducted by the inventors are described.

[0397] Summary of Study A and its results:

[0398] Study participants aged 55–60 years with subjective cognitive impairment (SCD) followed a 30-minute daily digital intervention protocol for two weeks. Participants were assessed using psychological questionnaires and resting-state fMRI (rsfMRI) at baseline and after the intervention.

[0399] The treatment protocol included maze navigation based on a standardized Hebb-Williams maze, as well as psychological and cognitive interventions such as CBT, psychoeducation, and guided imaging. The digitized maze utilized a combination of map-based (allocentric) and environment-based (egocentric) navigation. Navigation was first performed with eyes open, and then with blindfolded navigation assisted by a voice algorithm. This digitized maze experience was developed based on the inventors' research showing increased brain plasticity after blindfolded navigation training.

[0400] result: These changes were tracked using behavioral scores and brain imaging measured before training and after two weeks of training. Key findings: 1. rsfMRI showed increased connectivity after training between memory-related regions (hippocampal and parahippocampal regions within the medial temporal lobe (MTL)) and executive working memory frontal regions (anterior and posterior cingulate cortex within the frontoparietal network (FPN) and default mode network) (p<0.05, FDR corrected). 2. Improved connectivity significantly correlated with improved maze-solving performance after training.

[0401] After the intervention, an increase in rsFC between the MTL and the frontal executive area is observed.

[0402] Seed-voxel-based analysis revealed a significant increase in rsFC after training between the left and right hippocampal and parahippocampal regions within the medial temporal lobe (MTL), as well as in the frontoparietal network and the DMN network (Figures 8B-8C).

[0403] The most significant increase was observed in the left hippocampus and posterior cingulate cortex (PCC, BA31_R, k=328, P FDR <0.0001), inferior parietal cortex IPC (BA40, k=305, P FDR <0.0001) and posterior parietal cortex (BA5, k=356, P FDRA significant increase was observed in the rsFC between the left parahippocampal region and the dorsal prefrontal cortex (PFC, BA9_L) (k=176, P FDR =0.027). rsFC of the right parahippocampal region, anterior prefrontal cortex, and dorsal anterior cingulate cortex (dACC) (BA10_R, BA32_L; k=98, P FDR (=0.010, k=158, P=0.005) (Figure 4B). Importantly, this increase correlated with maze-solving performance (r=0.508, P=0.037), indicating a dynamic learning process (Figure 4C).

[0404] Figures 4A–4C show seed connectivity maps of longitudinal differences. Figure 4A shows seed: left hippocampus, and Figure 4B shows seed: right parahippocampus (resting-state brain imaging data post-intervention > pre-intervention - group levels. Add n=17 to all figures, etc., and descriptions and explanations), P<0.05, FDR corrected, parametric statistics, bilateral. Figure 4C shows the correlation between change in training score and increased PHA3-dACC post-training connectivity. With respect to the parahippocampus, PHA, dorsal anterior cingulate cortex, and dACC, Figures 4A–4C and Figure 6, the intervention of the present invention shows that post-training connectivity significantly increased between hippocampal and parahippocampal regions and between the frontoparietal network, including the executive function working memory frontal region (BA9, BA10), and the anterior and posterior cingulate cortex within the DMN (PCC, BA31, ACC, BA32). Furthermore, there is a significant correlation between post-intervention brain connectivity in the MTL-frontoparietal network and change in training score. The training score is calculated as: Final Maze APP Level / Total Training Time (hours).

[0405] The results showed significant improvements in post-training connectivity in allocentric and egocentric navigation brain regions, as well as in post-training connectivity between the insular cortex and these brain regions, reflecting healthier connectivity.

[0406] The intervention increased rsFC in regions correlated with egocentric and allocentric navigation.

[0407] Because the RSC integrates both egocentric and allocentric spatial information streams, increased connectivity was demonstrated in this important region after treatment. The rsFC between the right RSC seed and the right parietal cortex increased (k = 211, P FDR = 0.0017), contributing to egocentric navigation performance. Furthermore, an increase in rsFC was shown in the right anterior prefrontal cortex (BA10, k = 175, P FDR = 0.0038), which contributed to allocentric navigation performance.

[0408] Figures 5A - 5B show seed - voxel connectivity maps of longitudinal differences. The posterior splenial complex (RSC) that integrates both egocentric and allocentric spatial information streams is shown. Improved rsFC after training (post - trinng) was seen in both the egocentric and allocentric networks (k = 211, P FDR <0.002 and k = 175, P FDR <0.004). Seed: right RSC, (post - intervention > pre - intervention), parametric statistics, bilateral. Fisher's Z - effect - size connectivity values of clusters, error bars, CI. The intervention group shows that connectivity was significantly improved after training within the egocentric navigation network (RSC and parietal - frontal memory and executive network). The RSC is an important region connecting the egocentric and allocentric spatial memory networks (P < 0.05, FDR - corrected).

[0409] The intervention increased the rsFC between the spatial navigation network and the insular cortex.

[0410] In seed - voxel - based functional connectivity analysis, it was revealed that there was a significant increase in rsFC after training between the spatial navigation network and the granular anterior insular cortex seed (Figure 6). A significant increase was seen in the major regions of the egocentric network, namely, the pre - cuneus (BA7, k = 1172, PFDR <0.0001), lingual gyrus (BA19, k=630, P FDR <0.0001) and fusiform gyrus (BA37, k=111, P FDR In the area (=0.017), and in the major regions of the allocentric network, namely the medial prefrontal cortex, mPFC (BA32, k=101, P FDR These results were shown at 0.01. These results may be related to increased multisensory attention and self-awareness processes. The results may suggest that synergistic psychological and cognitive interventions increase connectivity between areas specialized in spatial and verbal memory (most closely associated with age-related degeneration) and limbic system structures such as the insula.

[0411] Figure 6 shows the longitudinal difference seed-voxel connectivity map. Increase in rsFC after training between the spatial navigation network and the insular cortex. Seed: left granular insular cortex. (Post-intervention > Pre-intervention), p<0.05, FDR corrected, parametric statistics, bilateral.

[0412] Post-training assessments showed a significant improvement in depression scores and a trend toward improvement in anxiety scores, with p=0.004 and 0.06, respectively.

[0413] This intervention significantly reduced self-reported depression. Following the intervention, CES-D (Depression Scale) scores decreased by 26.6% at the largest effect size (d=-0.829, p=0.004). A trend toward improvement was observed in anxiety scores (GAD7), with p=0.063 and d=-0.484.

[0414] Figure 7A shows the change in CES-D scores. This intervention resulted in a significant decrease in self-reported depression CES-D scores. Following the intervention, CES-D (depression scale) scores decreased by 26.6% at the largest effect size (d=-0.829, p=0.004). Data are presented with mean ± SEM, p-values, and paired student t-tests. Figure 7B shows the significant decrease in depression scores (CES-D) in the digital therapeutic intervention group (Remepy) compared to the control group.

[0415] In depression, there is often increased activity and connectivity within the default mode network (DMN) and the salience network (SN). Analysis in this study showed decreased network connectivity within the DMN (p=0.002), and a significant correlation was found between changes in depression scores and improved network connectivity between the DMN and SN (r=0.486, p=0.048), reflecting a healthier connectivity pattern.

[0416] The intervention improved the interconnections between the DMN and SN networks: ROI-ROI analysis revealed a decrease in intra-network connectivity within the DMN after the intervention (z-score: 0.64±0.28~0.59±0.23, P=0.002). No significant changes were observed within the SN (z-score: 0.62±0.27~0.60±0.27, P=0.169) (Figure 8C). No significant changes were observed between networks (z-score: -0.165±0.22~-0.160±0.21, P=0.126). However, a significant correlation was observed between changes in inter-network rsFC and changes in CES-D scores after treatment (r=0.486, P=0.048), indicating that improvement in depression scores correlates with increased inverse correlation between networks.

[0417] Figures 8A–8C show DMN-SN ROI-to-ROI network connectivity. Figure 8A shows that the default mode network (DMN) and salience network (SN) are inversely correlated in the brains of healthy, non-depressed individuals. Intra-network connectivity is shown in red, and inter-network connectivity is shown in blue. Figure 8B shows that improvement in CES-D depression scores (negative change indicates improvement in depressive state in post-hoc versus pre-hoc assessment) correlated with an increase in negative inter-network DMN-SN rsFC. This suggests a correlation between how much an individual subject improved in depression and how much healthier their connectivity pattern is (i.e., reflecting a greater inverse correlation between the DMN and SN (this inverse correlation is lost in depressed subjects)).

[0418] The results of this study highlight the synergistic effects between the unique cognitive and psychological interventions employed as part of this research.

[0419] DMN binding has previously been associated with psychological processes that influence inflammation, such as stress, anxiety, and depression, and several components of the DMN are known to control peripheral pathways that modulate inflammation.

[0420] The study also showed increased connectivity between the insular cortex and both egocentric and allocentric navigation networks after training.

[0421] The neurological and behavioral correlations of training older adults with subjective cognitive impairment using novel digital spatial memory and digital psychological interventions. This example of digital training in both egocentric and allocentric navigation employs a protocol demonstrating enhanced brain plasticity, namely a protocol for navigation using a stepwise blindfold and a rich multisensory environment. This example evaluates the impact of comprehensive digital psychocognitive multisensory training, focusing on behavior and resting-state functional connectivity (rsFC) in individuals with subjective cognitive impairment (SCD). Participants attended a two-week intervention consisting of daily 30-minute digital navigation training sessions featuring a digital version of the Hebb-Williams (HW) maze (specially adapted, with both allocentric (map-based) and egocentric (individual body-view-centered cues)), audiovisual navigation cues, a stepwise blindfold protocol, and stress-reducing psychological interventions. Study endpoints include brain rsFC, standardized questionnaires for psychological well-being and depression, HW maze performance scores, and correlations between various endpoint measurements.

[0422] The primary findings included: (1) a significant decrease in clinical CES-D depression scores (mean 27% decrease), which correlated with improved negative inter-network connectivity between the DMN (default mode network) and SN (salience network) and decreased inter-network connectivity within the DMN. Both of these changes are consistent with patterns observed in the literature for brain states presenting with fewer clinical depressive symptoms. (2) Enhanced connectivity was observed between the middle temporal lobe (MTL) region, particularly the hippocampus, and the prefrontal cortex of executive working memory. This improved connectivity was significantly correlated with enhanced spatial cognitive performance. (3) A significant increase in rsFC between egocentric and allocentric navigation regions and the insular cortex. The hippocampus and MTL are the structures most affected by aging and Alzheimer's disease (AD), and the above post-training changes are characteristic of brains that are less aged or less affected by clinical memory loss. These findings suggest that the combined, unique psycho-cognitive interventions and spatial memory blindfolding techniques resulted in major changes in spatial memory, spatial cognition, and emotional regulation domains, demonstrating key correlations between behavioral changes and brain connectivity.

[0423] Key points of the research: • A stronger inverse correlation was observed in DMN-SN binding after the intervention, indicating improved mood regulation through a better brain network function state. • Improvement in CES-D depression scores after intervention was significantly correlated with the brain connectivity patterns described above. • A blindfolded spatial memory training protocol enhances functional connectivity in brain regions sensitive to aging and degeneration of brain connectivity. • Improved spatial cognitive performance correlates with improved memory network connectivity, including in the middle temporal lobe (MTL) and egocentric navigation areas. • Multisensory psychocognitive digital training positively impacts connectivity in the MTL of spatial memory and in networks associated with frontal executive function. Improvements in Hebb-Williams (HW) multisensory and blindfolded training scores for spatial memory correlated with enhanced connectivity in both allocentric and egocentric navigation-related brain regions.

[0424] A longitudinal study was conducted to determine the effects of combined digital psycho-cognitive multisensory training on behavior and rsFC in older individuals experiencing subjective cognitive decline (SCD). In addition, correlations were observed between observed changes in rsFC and behavior.

[0425] Brain regions supporting spatial and verbal cognition are susceptible to premature damage during aging and neurodegenerative diseases. Egocentric and allocentric digital navigation training (visual use and blindfolded) has been shown to improve brain plasticity. Neuroinflammation and chronic stress are significant factors in brain degeneration during aging, MCI, and AD progression. Psychological interventions reduce inflammation and slow neurodegenerative diseases. Multisensory psychocognitive digital training improves brain plasticity, at least through synergistic effects.

[0426] Test design A pilot study designed as a prospective, open-label trial was conducted at the Baruch Ivcher Institute for Brain, Cognition & Technology (BCT) (School of Psychology at Reichman University, Israel). This study recruited healthy adults aged 55–60 years presenting with signs of subjective cognitive decline (SCD), a Montreal Cognitive Assessment (MoCA) score of 24 or higher, and a Perceptual Stress Scale (PSS-10) score of 5 or higher. Exclusion criteria included any history of malignancy, traumatic brain injury, brain surgery, chronic subdural hemorrhage, epilepsy and other neurodegenerative diseases, any psychiatric disorder or pathological cognitive decline, and contraindications to MRI. After signing informed consent, participants engaged in a two-week digital intervention using a mobile application, supplementing daily self-training at home with supervised sessions on days 1, 7, and 14. Participants were assessed for changes in brain functional and structural connectivity, MoCA cognitive assessment, well-being, and psychological state. This study was approved by the IDC Institutional Review Board (IRB) (No. P_2023138). The neuroimaging study protocol was reviewed and approved by the IRB at Sheva Medical Center (No. 8591-21-SMC). All participants signed informed consent prior to enrollment. All studies were conducted in accordance with relevant guidelines and regulations.

[0427] Digital intervention Participants utilize a comprehensive training mobile application developed by Remepy (https: / / www.remepy.com), which incorporates a unique methodology based on various factors, including the use of digital mazes (similar to Hebb-Williams mazes). The virtual navigation training protocol employs an innovative, integrated approach to spatial memory and navigation training, designed to accelerate the learning process and guide the balance of sensory and cognitive networks. The unique approach incorporated into Remepy's app combines both egocentric and allocentric navigation strategies through a three-stage blindfolded training protocol, with the complexity of navigation increasing in stages. Each new maze test begins with a top-down map of the maze, followed by a virtual 3D navigation experience with visual input. In the next step, navigation becomes more difficult as 50% of the maze is randomly masked, and in the final step, participants are asked to navigate the maze blindfolded, relying on spatial memory and auditory cues to convey critical spatial information (Figures 17A-17E). The primary task was to successfully find a path, but participants were instructed to find the fastest route to the exit while avoiding collisions with walls.

[0428] The distance audio algorithm utilizes frequency conversion, where higher frequencies indicate proximity to nearby walls, while lower frequencies indicate greater distance from walls. Footsteps indicate clear pathways. Participants guided their paths by swiping their fingers on the touchscreen in 45-degree directions. The software automatically logged errors, time, and performance for each session.

[0429] Maze-solving performance was calculated for each participant by dividing the final maze level achieved by the total training time. The training protocol scheme is provided therein.

[0430] The application also included mindfulness, attention-focusing exercises, and stress regulation techniques drawn from cognitive behavioral therapy, delivered in video, audio, and interactive formats. Daily self-training lasted approximately 30 minutes and included 20 minutes of participation in a navigation program and 5-10 minutes of psychological training (Figure 17E).

[0431] Figures 17A–17E illustrate the Remepy APP's comprehensive training mobile application. The top view map of the hardware maze used is shown (Figure 17A). It should be noted that the app utilizes a special version of the digital maze, including both a visually introduced allocentric view (Figure 17A) and a digital 3D egocentric navigation view with visual and auditory inputs (Figure 17B). In this way, participants were encouraged to integrate both map-based allocentric and egocentric navigation; a 50% random screening mask reduced half of the visual cues, and participants were encouraged to integrate visual cues with auditory cues (Figure 17C); blindfolded navigation where visual cues were unavailable (Figure 17D); and psychological interventions—video and audio aimed at chronic stress reduction, CBT, etc. (Figure 17E).

[0432] Outcome measurement Montreal Cognitive Assessment (MoCA) MoCA is a simple cognitive screening tool with high sensitivity and specificity for detecting MCI in patients. The maximum MoCA score is 30, and a score adjustment of 1 point is added for individuals with less than 12 years of education. Scores of 26 or higher were considered normal, and scores below 26 were considered the optimal cutoff point for diagnosing cognitive impairment.

[0433] Self-report questionnaire Changes in the psychological state of the subjects were assessed using validated questionnaires including the Mental Health Continuum Short Version (MHC-SF), the Generalized Anxiety Disorder 7-Item Scale (GAD-7), the Center for Epidemiological Research Depression Scale (CES-D), and the 36-Item Short Version Health Questionnaire (SF-36). These questionnaires were administered three times during the study (day 0, day 7, and day 14).

[0434] Brain imaging Brain imaging MRI scans were performed on a MAGNETOM Prisma 3T Scanner (Siemens Healthcare, Erlangen, Germany) configured with a 64-channel receiving head coil (Ruth and Meir Rosental Brain Imaging Center (MRI), Reichman University). The MRI protocol included the following sequences: Two resting-state fMRI scans totaling 300 volumes (9:28 mins) were acquired using the multiband echoplanar imaging sequence CMRR EPI 2D. Scan parameters: TR: 1,870 ms, TE: 30 ms, flip angle: 75°, voxel size: 3.0 x 3.0 x 2.0 mm, FOV: 192, slice count: 58 axial slices parallel to the AP-PC plane. During the scan, each participant was asked to remain still and relaxed, fix their gaze on the crosshairs, and refrain from thinking about anything intentional. Foam pads and earplugs were used to reduce head movement and scan noise. Structural T1-weighted MRI scans were acquired for co-registration purposes using a T1-weighted 3D magnetization-prepared rapid gradient-echo (MPRAGE) sequence in the sagittal section at 1 mm isotropic resolution. Sequence parameters: TR: 2,000 ms, TE: 1.9 ms, flip angle: 9°, TI: 920 ms, FOV: 256 × 256, and 176 consecutive slices. The MRI protocol also included T2-weighted fluid-suppressed inversion-recovery (FLAIR) and sensitivity-weighted imaging (SWI) sequences using standard parameters for clinical brain assessment.

[0435] BOLD Data Preprocessing Functional connectivity analysis was performed using the CONN-fMRI toolbox v22a, implemented with the statistical parametric mapping software SPM12 (http: / / www.fil.ion.ucl.ac.uk / spm). The functional volume preprocessing pipeline included realignment with susceptibility-strain interaction correction, slice timing correction, outlier detection, direct segmentation, and MNI spatial normalization, with a resolution voxel size of 2.0 × 2.0 × 2.0 mm, and included a spatial smoothing (8 mm FWHM Gaussian kernel) step. The preprocessing steps derived (1) realignment covariates including six rigid body parameters characterizing the estimated object motion, (2) scrubbing covariates including latent outlier scans performed with CONN's artifact detection tool (ART), and (3) quality assurance (QA) covariates based on global signal changes (standard deviation greater than 3 from mean image intensity) and frame-wise displacement (FD) inter-scan head motion. Age and sex were also used as group (second level) covariates. A component-based noise reduction (CompCor) approach was used to identify physiological noise, bold signals present in white matter, and additional confounding temporal factors controlling head motion effects.

[0436] Finally, the BOLD time series of the residuals were bandpass filtered in the frequency range of 0.01–0.009 Hz. Individual connectivity maps were generated using a seed-to-voxel approach. rsFC was examined using a priori seeds derived from the Extended HCP-MMP Atlas (HCPex). This Extended HCP-MMP Atlas (HCPex) is a modified and expanded version of the Human Connectome Project-MultiModal Parcellation Atlas (HCP-MMP), providing a surface-based version of 360 human cortical regions. Bivariate correlation analysis was used to determine the linear association of the BOLD time series between seeds and significant voxel clusters. Fisher's Z-transform was applied to the correlation coefficients to satisfy the normality assumption. Functional connectivity maps were then thresholded with a false discovery rate (FDR) P<0.05 corrected for multiple comparisons. ROI-to-ROI network analysis focused on commonly reported large brain networks associated with depression, including default mode (DMN) and salience (SN). Inter- and intra-network connectivity values ​​were computed using MATLAB R2021b (MathWorks, Natick, MA) to generate a symmetric node connectivity matrix. Finally, participants with head movements greater than 2 mm in any direction between volumes, rotations greater than 2° on any axis during scanning, or head movements with a mean FD greater than 0.5 in either the pre-processed or post-processed map were excluded from the dataset.

[0437] Statistical analysis - descriptive statistics Continuous demographic and clinical data are presented as mean ± standard deviation (SD). Two-tailed independent t-tests were performed to compare variables between groups, with the assumption of normality maintained by the Kolmogorov-Smirnov test. Categorical data are presented numerically and as percentages. To assess the effect of interventions, Student's t-tests were used to compare post-processed and pre-processed data. Effect sizes were assessed using Cohen's d-method. Data analysis was performed using the Statistics and Machine Learning Toolbox in MATLAB R2021b (MathWorks, Natick, MA).

[0438] Image Analysis Statistics At the group level, seed-to-voxel resting-state functional connectivity (rsFC) was analyzed using a repeated measures model to examine the effects of the intervention. The analysis was implemented using SPM software (version 12, UCL, London, UK) and a parametric analysis approach across the entire brain volume. rsFC was considered significant at a connectivity probability threshold of 0.001 at the voxel level, and at the cluster level with a false detection rate p<0.05 using the Benjamini-Hochberg FDR method corrected for multiple comparisons across the whole brain, as well as at a minimum cluster size of 50 voxels. The REX toolbox was used to extract cluster connectivity statistics. Spearman rank correlation was used to examine associations with cognitive and behavioral scores.

[0439] result Participant demographics and recruitment Of the 20 individuals evaluated for eligibility, two were excluded due to claustrophobia, and one withdrew from participation by withdrawing consent. As a result, the study proceeded with 17 participants.

[0440] Decrease in self-reported depression The questionnaire analysis is summarized in Table 1. Following the intervention, the CES-D (Depression Scale) score decreased by 26.6% at the largest effect size (d=-0.829, p=0.004) (Figure 7). A trend toward improvement was observed in the anxiety score (GAD7), with p=0.063 and d=-0.484. No significant changes were observed in quality of life and well-being measurements.

[0441] Figure 7 shows the changes in CES-D scores. This intervention significantly reduced self-reported depression on the CES-D questionnaire. Following the intervention, CES-D (depression scale) scores decreased by 26.6% at the largest effect size (d=-0.829, p=0.004). Data are presented with mean ± SEM, p-values, and paired Student's t-test analysis. [Table 1]

[0442] SF-36, 36-item shortened questionnaire; MHC-SF, shortened version of the Mental Health Continuum; CES-D, Center for Epidemiological Research Depression Scale; GAD-7, Generalized Anxiety Disorder 7.

[0443] Improved DMN and SN Network Interaction ROI-to-ROI network analysis revealed a decrease in intra-network connectivity within the DMN after intervention, with the z-score decreasing from 0.64±0.28 to 0.59±0.23, achieving statistical significance (p<0.002, Figure 8B). In contrast, no significant change was observed in SN connectivity, with the z-score changing slightly from 0.62±0.27 to 0.60±0.27, failing to reach statistical significance (p=0.169). Furthermore, no significant change was revealed in inter-network connectivity between the DMN and SN, with the z-score slightly adjusted from -0.165±0.22 to -0.160±0.21 (p=0.126). However, a significant correlation was found between changes in inter-network rsFC and changes in CES-D scores after intervention (r=0.486, p<0.05), indicating that the improvement in depression scores correlated with increased inter-network inverse correlations.

[0444] Figures 8A–8C show DMN-SN ROI-to-ROI network connectivity. They demonstrate that the default mode network (DMN) and salience network (SN) are inversely correlated in the brains of healthy, non-depressed individuals. Intra-network connectivity is shown in red, and inter-network connectivity is shown in blue. The decrease in intra-network connectivity within the DMN after intervention (z-score: 0.64±0.28 to 0.59±0.23, p<0.002) is observed. Improvements in CES-D depression scores (negative changes indicate improvement in depressive state in post-hoc versus pre-hoc assessments) correlated with an increase in negative inter-network DMN-SN rsFC. This suggests a correlation between the degree of improvement in depression in individual subjects and the degree to which their connectivity patterns became healthier (i.e., a reflection of separation between the DMN and SN (this inverse correlation is lost in depressed subjects)).

[0445] Increase in rsFC between MTL and the frontal executive area after intervention. Seed-voxel-based analysis revealed a significant increase in rsFC after training between the left and right hippocampal and parahippocampal regions within the medial temporal lobe (MTL), as well as between the frontoparietal network and the DMN network (Figures 8A-8C).

[0446] The most significant increase in rsFC was observed in the left hippocampus and posterior cingulate cortex (PCC, BA31_R, k=328, p FDR <0.0001), inferior parietal cortex IPC (BA40, k=305, p FDR <0.0001) and posterior parietal cortex (BA5, k=356, p FDR A significant increase was observed between <0.0001) (Figure 4A). A significant increase in rsFC was observed between the left parahippocampal region and the dorsal prefrontal cortex (PFC, BA9_L) rsFC (k=176, p FDR This was also shown between the right parahippocampal region and the anterior prefrontal cortex and dorsal anterior cingulate cortex (dACC) (BA10_R, BA32_L; k=98, p = 0.027), and also between the right parahippocampal region and the anterior prefrontal cortex and dorsal anterior cingulate cortex (dACC) (BA10_R, BA32_L; k=98, p = 0.027 FDR =0.010, k=158, p FDR This was also shown between r=0.005 (Figure 4B). Importantly, this increase correlated with maze-solving performance (r=0.508, p<0.05), indicating a dynamic learning process (Figure 4C).

[0447] Figures 4A-4C show seed connectivity maps of longitudinal differences. Seed: left hippocampus. Seed: right parahippocampus. Resting-state brain imaging data: post-intervention > pre-intervention - group level. n=17, p<0.05, FDR corrected, parametric statistics, bilateral. Figure 4C shows the correlation between changes in training scores and increased PHA3-dACC connectivity after training. Parahippocampus, PHA, dorsal anterior cingulate cortex, dACC.

[0448] Increased rsFC in regions correlated with egocentric and allocentric navigation. Since the RSC integrates both egocentric and allocentric spatial information streams, increased connectivity in this critical region was demonstrated after treatment. The rsFC between the right RSC seed and the right parietal cortex increased (k=211, p FDR<0.002), which may contribute to egocentric navigation performance. Furthermore, increased rsFC may contribute to the right anterior prefrontal cortex (BA10, k=175, p FDR As shown in <0.004), this may contribute to allocentric navigation performance (Figure 5). n=17, p<0.05, FDR corrected, parametric statistics, two-tailed.

[0449] Figures 5A and 5B show seed-voxel connectivity maps of longitudinal differences. The posterior cingulate cortex complex (RSC) integrates both egocentric and allocentric spatial information streams. Post-training improvements in rsFC were observed in both egocentric and allocentric networks (k=211, p, respectively). FDR <0.002 and k=175, p FDR <0.004). Seed: Right RSC, n=17, post-intervention > pre-intervention, parametric statistics, two-tailed. Fisher's Z effect size of clusters, bondability values, error bars, CI.

[0450] Increased rsFC between the spatial navigation network and the insular cortex. Seed-voxel based functional connectivity analysis revealed a significant increase in post-training rsFC between the spatial navigation network and granular insula cortex seeds (Figure 6). The significant increase was observed in the major region of the egocentric network: precuneus (BA7, k=1172, p FDR <0.0001), lingual gyrus (BA19, k=630, p FDR <0.0001) and fusiform gyrus (BA37, k=111, p FDR In <0.02), and in the major regions of the allocentric network: medial prefrontal cortex mPFC (BA32, k=101, p FDRThese results were shown in <0.01). These results may be related to increased multisensory attention and self-awareness processes. The results may suggest that synergistic psychological and cognitive interventions increase connectivity between areas specialized in spatial and verbal memory (most closely associated with age-related degeneration) and limbic system structures such as the insula.

[0451] Figure 6 shows the longitudinal difference seed-voxel connectivity map. Increase in rsFC between the spatial navigation network and the insular cortex after training. Seed: left granular insular cortex. n=17, post-intervention > pre-intervention, parametric statistics, bilateral.

[0452] Consideration In this proof-of-concept study, the effects of a two-pronged intervention utilizing psychological strategies targeting chronic stress and spatial memory training to enhance neuroplasticity can be seen in the relevant psychological outcomes and the brain regions associated with these functions. The intervention employs an innovative protocol that transitions from visual cues to auditory cues, uniquely incorporating both allocentric and egocentric navigation techniques through a digital hardware maze, mimicking the effects of blindfolding.

[0453] Participants followed a two-week protocol of 30 minutes of digital intervention daily and were assessed before and after training using psychological questionnaires and rsFC. The primary outcomes presented were: 1. Positive impact on clinical depression scores (Figure 7); 2. Improved network connectivity within the DMN (healthier / less depressive) (Figure 8B); 3. Correlation between changes in depression scores and increased negative network connectivity between the DMN and SN (Figure 8C); 4. Increased connectivity between memory-related areas of the MTL and the prefrontal cortex of executive working memory, which also correlated with the overall spatial memory HW maze solving performance index (Figure 4C).

[0454] Ultimately, a significant increase in connectivity7 between allocentric and egocentric navigation regions was found7 (Figure 5). Taken together, these results suggest that synergistic psychological-cognitive interventions combined with the blindfold protocol significantly influence specific brain plasticity and behavioral changes. The results indicate that digital interventions can produce positive changes in both psychocognitive ability and connectivity in brain regions that support spatial and verbal memory (regions most sensitive to aging and early AD).

[0455] This study used functional neuroimaging to measure specific large-scale modulations of synaptic connectivity and neuroplasticity, and a series of psychological questionnaires to identify changes in visuospatial performance and psychological state. The study was conducted on 55-60 year old subjects with self-reported SCD and employed a unique virtual version of the classical Hebb-Williams labyrinth multisensory reinforcement environment protocol. This protocol aimed to induce rapid neuroplasticity and increase connectivity, as seen in sensory substitution studies and blindfold and sensory deprivation studies.

[0456] Firstly, these findings provide empirical proof of concept for the hypothesis that short-term exposure to a virtual HB maze in a multisensory reinforcement environment, combined with a gradually blindfolding protocol that integrates both allocentric and egocentric cues and complementary stress-reducing psychological interventions, effectively promotes neuroplasticity and enhances psychological well-being in a highly specific and predictive manner. This creates a synergistic effect, forming a platform for enhancing brain plasticity throughout life by integrating digital psychological and cognitive multisensory training. This approach could be used in subjects with neurodegenerative processes in the aging brain, as this combined strategy can specifically target and modulate brain regions particularly vulnerable to aging, such as the MTL and DMN, as well as modulate their connectivity with other brain regions.

[0457] In conclusion, this disclosure demonstrates that a gradual cross-modal blindfold navigation approach incorporating both egocentric and allocentric strategies, combined with coupled psycho-cognitive chronic stress reduction interventions, produces synergistic effects on the aging brain when sustained. Both of these outcomes, namely behavioral and connectivity patterns, support coupled interventions for reducing inflammation and slowing the progression of degenerative brain disease. Furthermore, by pushing the boundaries of critical period theories for brain plasticity in aging individuals, this study suggests that daily digital interventions via relatively short (several weeks) self-training protocols can induce highly dramatic changes in brain connectivity within areas critical to spatial and verbal memory, areas that are often vulnerable in the early stages of AD.

[0458] Example 2 SCD follow-up study "Study B" (interim analysis) Follow-up study "Study B" (Interim analysis) A follow-up study was conducted in adults with elevated stress levels and SCD, and 102 participants were randomized to either an intervention or a waitlist control group. The intervention group followed a 30-minute daily digital treatment protocol for three weeks. The treatment protocol consisted of a modified, combined intervention that placed greater emphasis on stress-reducing psychological modules in addition to the multisensory maze navigation training described above.

[0459] Participants were assessed at baseline and after the intervention using psychological questionnaires, immune system biomarkers, and fMRI. The intervention group was further assessed at 3 weeks post-intervention.

[0460] The results of the psychological questionnaire showed significant improvements in scores for depression (CES-D, p=0.22, see Figure 10A), stress / anxiety (STAI-S, p=0.028, see Figure 10B), resilience (BRCS, p=0.025, see Figure 10C), and emotional well-being (MHC-SF, p=0.043, see Figure 10D) in the intervention group compared to the control group. Furthermore, significant marginal improvements were observed in additional measures of stress and anxiety (PSS, see Figure 10E; STAI-T, see Figure 10F).

[0461] Improvements in questionnaire scores were maintained or further improved in the intervention group at the 3-week assessment after the end of daily use of the mobile application, highlighting the sustained effect of the intervention. Figures 11A–11F show bar graphs recording the maintained or further improved questionnaire score improvements in the intervention group at the 3-week assessment after the end of daily use of the mobile application, highlighting the sustained effect of the intervention. Subgroups of participants from both the intervention and control groups were assessed by rsfMRI at baseline and after the intervention to evaluate brain network connectivity.

[0462] Example 3 Digital intervention Further examples (non-exclusive) of additional digital interventions are provided, namely interventions that directly affect the brain and improve spatial and verbal memory, cognition, etc.

[0463] Sound and Vibration Sequence: In a specific order, each ear receives a unique sound, and each wrist vibrates in a different form. The goal is to memorize the longest possible signal sequence. This digital intervention is based on the "Simon Memory Game" with minor modifications, but instead of using auditory and visual perception, the subject uses auditory and tactile perception. The sequence begins with one signal, and the subject is asked to repeat it. After a correct response, the first signal is followed by another signal. A voice recognition system allows the app to follow the subject's responses.

[0464] 3D Music: After listening to the music, the subject is asked to point with their hand to the direction of each instrument. The subject not only needs to identify the direction of each instrument, but also needs to remember that direction until the end of the song.

[0465] Examples of (non-exclusive) digital interventions used, namely interventions that modulate the immune system, are described herein.

[0466] Mindful breathing. Participants are guided to breathe deeply (diaphragmatic breathing) using sounds associated with their breath. Feedback from measured respiratory rate, heart rate, etc., can also be included. Mindful breathing involves focusing attention on the sensation of breath entering and leaving the body, without judgment or distraction. For example, sit comfortably, close your eyes, consciously observe the rise and fall of your abdomen with each inhale and exhale, and gently return your attention to your breath when your mind wanders.

[0467] Drug-specific guided imagery. Participants are guided to imagine the effects of the drug within their own bodies. Various sensory cues are provided to help the participant anticipate the effects, for example, to help manage expectations or reduce anxiety. This can be implemented through vivid mental imagery to enhance the drug's effectiveness by visualizing its positive impact on the body's healing processes. For example, a patient prescribed antibiotics might close their eyes and imagine the drug as a powerful army fighting and eliminating harmful bacteria, while simultaneously experiencing feelings of relief and recovery in the affected area. This can also be combined with specific digital interventions that associate similar emotions with the participant.

[0468] Body scan. Participants are guided to perform a systematic body scan (perhaps with a greater focus on areas of the body that are particularly painful). The training may involve any sensory cues, such as sounds emanating from the body part being asked to be focused on, or AR / VR visuals directed towards that specific body part. For example, someone practicing a body scan might start with their feet and gradually move upwards, paying close attention to sensations such as warmth, numbness, or tension, and as they become aware of them, gently release any areas of stiffness or discomfort. Digital platforms can be implemented to conduct the body scan.

[0469] Progressive muscle relaxation. Similar to a body scan, but here it involves progressive muscle relaxation. The focus can range from small muscle groups to larger body parts. Participants may begin by tensing the muscles in their legs for a few seconds, then releasing the tension, focusing on the sensation of relaxation spreading through their feet and toes.

[0470] 5-4-3-2-1 exercise. Participants are instructed to focus on five things they can see, four things they can hear, three things they can feel, two things they can smell, and one thing they can taste.

[0471] Attention training techniques. These generally involve exercises designed to enhance focus and concentration by directing attention to a specific stimulus or task, while minimizing distractions. For example, a participant might be presented with a distinct soundscape moving through space (e.g., a waterfall or an owl). The participant might be instructed to focus their attention on the specific soundscape and track it for a certain period of time (e.g., 90 seconds), and then be instructed to focus their attention on a different soundscape.

[0472] Values ​​training. Building on previously conducted values ​​checklist training, this focuses on a reminder of this value, its value, and what you want to do to get closer to that value. Using this particular digital intervention via VR can potentially leverage the visual experience of the value (e.g., family, friends). Values ​​checklist training: Select important values ​​(they are those you choose to "get closer" to, accompanied by sound). Next, choose one. Next, think about the areas of life in which you would like to express this value more.

[0473] Psychoeducation. This includes various psychoeducational modules on chronic conditions and their associated symptoms, covering physiological explanations of neurodegenerative diseases, pharmacotherapy (e.g., immunotherapy), the role of thought and other top-down processes in generating symptoms, and how mental interventions can be helpful. Additionally, there are modules on how digital interventions and their combination with medications work. Some modules may utilize VR visualizations.

[0474] Maladaptive thought pattern identification exercise. An exercise in which the patient needs to identify their own maladaptive thought patterns.

[0475] Example 4 Effects on immune system biomarkers This disclosure demonstrates the effectiveness of digital therapeutic interventions on immune system biomarkers.

[0476] Figure 12A shows the effect of digital intervention on IL-17. IL-17 is associated with depression and may be a biomarker of reduced response to antidepressants. Clinical trials investigating the efficacy and safety of monoclonal antibodies against IL-17 are currently underway in treatment-resistant depression, as shown in Figure 12A (e.g., "chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories"). IL-17 can upregulate PD-1 expression, reducing response and mediating resistance to PD-1 blockade. IL-17 inhibitors and PD-1 blockade work together to establish antitumor effects.

[0477] IL-18 is associated with inflammation and depression, stimulating the production of IFN-γ and inflammatory cytokines, and influencing neural networks that modulate motivation and reward processing in depression. Figure 12B shows ...

Claims

1. A method for increasing neural connectivity in an individual, wherein the method is A method comprising the individual performing at least one digital intervention from among sensory inhibition, sensory substitution, sensory integration, or a combination thereof.

2. The method according to claim 1, wherein the at least one digital intervention is included in a digital therapeutic intervention plan.

3. The method according to claim 1, wherein the digital intervention comprises at least one psychological intervention, at least one cognitive intervention, at least one physical intervention, or a combination thereof.

4. The method according to claim 1, wherein the at least one digital intervention is performed at least partially on a personal electronic device.

5. The method according to claim 2, further comprising transferring data for the said individual, wherein the data is selected from personal information, demographic information, medical information, biomarker information, drug intake and medication regimens, geographic information, environmental information, lifestyle information, health and well-being, biometric information, behavioral information, digital intervention-related data, goal setting, medical considerations, health and well-being, preferences, availability, time constraints, scheduling, individual strengths and weaknesses, cultural considerations, communication channel preferences, feedback from the said individual, feedback from healthcare providers, or a combination thereof.

6. The method according to claim 5, further comprising analyzing data by machine learning, artificial intelligence (AI), statistical modeling, or a combination thereof, in order to adapt the digital therapeutic intervention plan.

7. The method according to claim 6, wherein the degree of improvement achieved by the individual implementing the digital therapeutic intervention plan is determined by the analysis.

8. The method according to claim 2, further comprising providing instructions to the individual before, during, and / or after any stage of the digital therapeutic intervention plan.

9. The method according to claim 3, wherein the at least one psychological intervention is selected from guided imaging, psychoeducation, psychotherapy, cognitive behavioral therapy, stress and anxiety management training, mindfulness-based intervention, body scanning training, sleep hygiene, fatigue training, acceptance and commitment therapy (ACT), dialectical behavior therapy (DBT), psychodynamic therapy, solution-focused brief therapy (SFBT), narrative therapy, pain therapy, addiction therapy, gestalt therapy, behavioral activation therapy, telepsychiatry and teletherapy, or a combination thereof.

10. The method according to claim 3, wherein the at least one cognitive intervention is selected from maze navigation, spatial navigation, Magic 7 training, memory enhancement techniques, attention training, problem solving, sonification exercises, data visualization, geometric puzzles, shape and pattern matching, visual cognitive tasks, spatial reasoning games, face detection training, drawing games, concentration training, reading comprehension training, or any combination thereof.

11. The method according to claim 3, wherein the at least one physical intervention is selected from physiotherapy, voice therapy, speech therapy, swallowing therapy, breathing training, saliva and drooling therapy, chewing therapy, facial expression training, tremor management, mobility training, freeze and stiffness exercises, tapping training, limb agility exercises, volume-sustain-pitch training, training for gait freeze, motor function therapy, dance therapy, handwriting training, balance exercises, postural stability training, muscle training, stretching exercises, coordination training, metronome training, fine motor skills training, or a combination thereof.

12. The method according to claim 10, wherein the maze is selected from a Hebb-Williams maze, a Morris water maze, a Burns maze, a radial arm maze, a T-maze, and an elevated plus maze.

13. The method according to claim 1, wherein the sensory inhibition includes at least partial inhibition of at least one sensory modal input.

14. The method according to claim 13, wherein the at least one sensory modality input is selected from visual, auditory, and tactile.

15. The method according to claim 1, wherein the sensory substitution includes at least partial substitution of at least one sensory modality input with at least one other sensory modality input.

16. The at least partial substitution of the at least one sensory modality input by at least one other sensory modality input is From sight to hearing and / or touch, From hearing to sight and / or touch, The method according to claim 15, selected from touch, sight, and / or hearing.

17. The method of claim 1, wherein the sensory integration includes at least a partial combination of at least two sensory modal inputs.

18. The method according to claim 17, wherein the at least two sensory modal inputs are selected from visual, auditory, and tactile.

19. The method according to claim 4, wherein the digital intervention includes the individual interacting with a personal electronic device using any of the following means selected from touch gestures, motion gestures, voice commands, text input, interaction with cameras and media, sensor-based interaction, or a combination thereof.

20. The method according to claim 19, wherein the touch gesture is selected from tapping, swiping, scrolling, pinching, dragging, double tapping, or a combination thereof.

21. The method according to claim 19, wherein the motion gesture is selected from tilting, shaking, rotating, body movement, waving, or a combination thereof.

22. The method according to claim 19, wherein the camera and / or media interaction is selected from taking photographs, recording videos, uploading / downloading images, uploading / downloading audio, uploading / downloading videos, augmented reality, or a combination thereof.

23. The method according to claim 19, wherein the interaction based on the sensor is performed by any of the following: a global positioning system (GPS) system, an accelerometer, a gyroscope, a proximity sensor, or a combination thereof.

24. The method according to claim 1, wherein the at least one digital intervention is carried out in any form of an instructional video, an interactive video including input and feedback from the individual, a game, an instructional prompt, a question-and-answer survey with feedback, virtual reality, augmented reality, or a combination thereof.

25. The method according to claim 3, wherein the at least one psychological intervention, the at least one cognitive intervention, the at least one physical intervention, or a combination thereof, extends for a period ranging from one second to 60 minutes.

26. The method according to claim 2, wherein the digital therapeutic intervention plan is implemented over a period of time from one day to ten years.

27. The method according to claim 5, further comprising an adaptation plan during the process of the digital therapeutic intervention plan, Receiving the aforementioned data, Receiving data updated in accordance with the at least one psychological intervention, the at least one cognitive intervention, the at least one physical intervention, or a combination thereof, Analyzing data and updated data using machine learning, artificial intelligence (AI), or statistical modeling, A method comprising generating an updated digital therapeutic intervention plan for the individual in response to an analysis of the updated data.

28. The method according to claim 27, wherein the adaptation includes a change in any of the following, selected from the type of intervention, the order of interventions, the frequency of interventions, the intensity of interventions, the length of interventions, the difficulty of interventions, the sensory modal inputs used, the level of interaction, or a combination thereof.

29. The method according to claim 4, further comprising at least one additional device selected from a health monitoring system, haptic device, external speaker, headphones, virtual reality set, augmented reality glasses / device, biofeedback sensor, wearable activity tracker, smartphone, personal computing device, smart speaker, voice assistant, motion tracking sensor, virtual assistant system, internet hub, or a combination thereof, wherein the at least one additional device is configured to transfer data between the individual, the personal electronic device, or a combination thereof.

30. The method according to claim 29, wherein the health monitoring system is selected from a wearable fitness tracker, a remote patient monitoring (RPM) system, a telemedicine platform, a smart health device, a health and wellness app, and a hospital information system (HIS).

31. The method according to claim 29, wherein the at least one additional device is configured to provide at least one of the following: real-time feedback to the individual based on collected data and interactions, measuring health parameters, outputting signals to the individual, customizing a digital therapeutic intervention plan in real time, monitoring the individual's engagement with and adherence to a therapeutic protocol, providing remote monitoring, inter-device cloud synchronization and data sharing, or a combination thereof.

32. The method according to claim 29, wherein the personal electronic device, the at least one additional device, or a combination thereof is configured to provide a sensory modal input for performing the sensory suppression, the sensory substitution, the sensory integration, or a combination thereof.

33. The method according to claim 1, for treating, preventing, or alleviating symptoms in an individual suffering from a neurodegenerative disease.

34. The method according to claim 33, wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, chronic traumatic encephalopathy (CTE), Lewy body dementia (LBD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), Huntington's disease, Creutzfeldt-Jakob disease, and Wilson's disease.

35. The method according to claim 1 for treating, preventing, or alleviating symptoms in an individual suffering from a neurological disorder.

36. The method according to claim 35, wherein the neurological disorder is selected from mild cognitive impairment (MCI), sleep disorders, migraines and headache disorders, neuropathy, epilepsy, traumatic brain injury, spinal cord injury, and cerebrovascular disease.

37. The method according to claim 1, for treating, preventing, or alleviating symptoms in an individual suffering from a psychological disorder.

38. The method according to claim 37, wherein the psychological disorder is selected from depression, anxiety, bipolar disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), attention-deficit / hyperactivity disorder (ADHD), eating disorders, substance use disorders, sleep disorders, autism spectrum disorder (ASD), personality disorders, schizophrenia, and dissociative disorders.

39. The method according to claim 1, further comprising administering at least one non-digital medical intervention before, during, or after at least one digital intervention, or a combination thereof.

40. The method according to claim 39, wherein the non-digital medical intervention is selected from pharmaceuticals, medical procedures, physiotherapy, psychotherapy, psychiatry, rehabilitation, lifestyle interventions, nutritional supplements, mineral supplements, and physical exercise.

41. The method according to claim 40, wherein the pharmaceutical agent is selected from dopaminergic agents, anti-amyloid beta antibodies, opioids, immune checkpoint inhibitors, NMDA receptor antagonists, triptans, acetylcholinesterase inhibitors, neurosteroids, anti-inflammatory agents, neuroprotective agents, mitochondrial support agents, metabolic therapies, hormone therapies, tau-targeted therapies, beta-secretase inhibitors, gamma-secretase modulators, or combinations thereof.

42. The method according to claim 41, wherein the dopaminergic agonist is selected from a dopamine precursor, a dopamine agonist, a monoamine oxidase inhibitor (MAOI), or a combination thereof.

43. The method according to claim 42, wherein the dopamine precursor is selected from levodopa, levodopa-carbidopa, levodopa-benserazide, levodopa-carbidopa-entacapone, foslevodopa-foscarbidopa, or a combination thereof.

44. The method according to claim 42, wherein the dopamine agonist is selected from pramipexole, ropinirole, rotigotine, apomorphine, bromocriptine, cabergoline, pergolide, lislide, or a combination thereof.

45. The method according to claim 42, wherein the monoamine oxidase inhibitor is selected from selegiline, rasagiline, safinamide, or a combination thereof.

46. The method according to claim 41, wherein the anti-amyloid-beta antibody is selected from lecabemab, aducanumab, solanezumab, gantenerumab, crenezumab, donanemab, or a combination thereof.

47. The method according to claim 41, wherein the opioid is selected from morphine, fentanyl, oxycodone, hydrocodone, buprenorphine, codeine, hydromorphone, meperidine, tapentadol, butorphanol, pethidine, levorphanol, methadone, dextropropoxifen, tramadol, ketobemidone, or a combination thereof.

48. The method according to claim 41, wherein the immune checkpoint inhibitor is selected from PD-1 inhibitors, pembrolizumab, nivolumab, semiprimab, PD-L1 inhibitors, avelumab, atezolizumab, durvalumab, CTLA-4 inhibitors, ipilimumab, tremelimumab, LAG-3 inhibitors, relatrimab, TIM-3 inhibitors, sabatrimab, TIGIT inhibitors, tiragolumab, domvanarimab, CD40 agonists, sericrelumab, OX40 agonists, utomirumab, GITR agonists, tiragolumab, IDO1 inhibitors, VISTA inhibitors, B7-H3 inhibitors, or combinations thereof.

49. The NMDA receptor antagonists include SAGE-718, memantine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N). ２ The method according to claim 41, wherein the method is selected from o), ketamine, or a combination thereof.

50. The method according to claim 41, wherein the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine, galantamine, or a combination thereof.

51. The method according to claim 41, wherein the neurosteroid is selected from allopregnanolone, dehydroepiandrosterone, pregnenolone, progesterone, androstenediol, estradiol, testosterone, or a combination thereof.

52. The method according to claim 40, wherein the anti-inflammatory agent is selected from nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, biological agents, or combinations thereof.

53. The method according to claim 41, wherein the anti-inflammatory agent is selected from ibuprofen, naproxen, aspirin, celecoxib, diclofenac, prednisone, hydrocortisone, dexamethasone, prednisolone, methylprednisolone, tumor necrosis factor (TNF) inhibitors, interleukin (IL) inhibitors, Janus kinase (JAK) inhibitors, interleukin-1 (IL-1) receptor antagonists, interleukin-6 (IL-6) inhibitors, interleukin-17 (IL-17) inhibitors, biological disease-modifying antirheumatic drugs (DMARDs), colchicine, or a combination thereof.

54. The method according to claim 41, wherein the neuroprotective agent is selected from allopregnanolone, dehydroepiandrosterone, pregnenolone, progesterone, androstenediol, estradiol, testosterone, ketamine, riluzole, antioxidants, vitamin E, vitamin C, alpha-lipoic acid, omega-3 fatty acids, coenzyme Q10 (CoQ10), ginkgo biloba extract, melatonin, resveratrol, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glutathione, magnesium, L-carnitine, carnosine, N-acetylcysteine ​​(NAC), curcumin, quercetin, green tea extract, bacopa monnieri, ginseng, huperzine A, or a combination thereof.

55. The method according to claim 41, wherein the nutritional supplement is selected from vitamin B, vitamin B12, omega-3 fatty acids, magnesium, zinc, iron, folic acid, vitamin C, vitamin E, probiotics, ginkgo biloba, curcumin, coenzyme Q10, acetyl-L-carnitine, alpha-lipoic acid, phosphatidylserine, bacopa monnieri, ashwagandha, rhodiola rosea, L-theanine, melatonin, or a combination thereof.

56. The method according to claim 40, wherein the pharmaceutical agent is administered by injection, oral, topical, inhalation, transdermal, nasal, intravenous, intramuscular, subcutaneous, or a combination thereof.

57. The method according to claim 6, wherein the digital therapeutic intervention plan is further configured to take into account the individual's drug intake, medication regimen and non-digital medical intervention schedule in order to achieve the increase in neural connectivity.

58. The method according to claim 40, wherein the at least one digital intervention, pharmaceutical agent, or combination thereof is administered together with a conditioned stimulus selected from visual, auditory, tactile, or combination thereof.

59. The method according to claim 1, further comprising gamification elements.

60. The method according to claim 59, wherein the gamification element is selected from badges, scores, leaderboards, rankings, game currency, quests or missions, characters or avatars, virtual goods, social media features, experience points (XP), or a combination thereof.

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